Antibody molecules to pd-1 and uses thereof

ABSTRACT

Antibody molecules that specifically bind to PD-1 are disclosed. The anti-PD-1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 15/595,618, filed May 15, 2017, now allowed, which is a divisionalapplication of U.S. application Ser. No. 14/604,415, filed Jan. 23,2015, now U.S. Pat. No. 9,683,048, issued Jun. 20, 2017, which claimsthe benefit of U.S. Provisional Application No. 61/931,512, filed Jan.24, 2014, U.S. Provisional Application No. 62/059,676, filed Oct. 3,2014, and U.S. Provisional Application No. 62/094,834, filed Dec. 19,2014. The contents of the aforementioned applications are herebyincorporated by reference in their entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jan. 12, 2015, isnamed C2160-700010_SL.txt and is 186,670 bytes in size.

BACKGROUND

The ability of T cells to mediate an immune response against an antigenrequires two distinct signaling interactions (Viglietta, V. et al.(2007) Neurotherapeutics 4:666-675; Korman, A. J. et al. (2007) Adv.Immunol. 90:297-339). First, an antigen that has been arrayed on thesurface of antigen-presenting cells (APC) is presented to anantigen-specific naive CD4⁺ T cell. Such presentation delivers a signalvia the T cell receptor (TCR) that directs the T cell to initiate animmune response specific to the presented antigen. Second, variousco-stimulatory and inhibitory signals mediated through interactionsbetween the APC and distinct T cell surface molecules trigger theactivation and proliferation of the T cells and ultimately theirinhibition.

The immune system is tightly controlled by a network of costimulatoryand co-inhibitory ligands and receptors. These molecules provide thesecond signal for T cell activation and provide a balanced network ofpositive and negative signals to maximize immune responses againstinfection, while limiting immunity to self (Wang, L. et al. (Epub Mar.7, 2011) J. Exp. Med. 208(3):577-92; Lepenies, B. et al. (2008)Endocrine, Metabolic & Immune Disorders—Drug Targets 8:279-288).Examples of costimulatory signals include the binding between the B7.1(CD80) and B7.2 (CD86) ligands of the APC and the CD28 and CTLA-4receptors of the CD4⁺ T-lymphocyte (Sharpe, A. H. et al. (2002) NatureRev. Immunol. 2:116-126; Lindley, P. S. et al. (2009) Immunol. Rev.229:307-321). Binding of B7.1 or B7.2 to CD28 stimulates T cellactivation, whereas binding of B7.1 or B7.2 to CTLA-4 inhibits suchactivation (Dong, C. et al. (2003) Immunolog. Res. 28(1):39-48;Greenwald, R. J. et al. (2005) Ann. Rev. Immunol. 23:515-548). CD28 isconstitutively expressed on the surface of T cells (Gross, J., et al.(1992) J. Immunol. 149:380-388), whereas CTLA-4 expression is rapidlyup-regulated following T-cell activation (Linsley, P. et al. (1996)Immunity 4:535-543).

Other ligands of the CD28 receptor include a group of related B7molecules, also known as the “B7 Superfamily” (Coyle, A. J. et al.(2001) Nature Immunol. 2(3):203-209; Sharpe, A. H. et al. (2002) NatureRev. Immunol. 2:116-126; Collins, M. et al. (2005) Genome Biol.6:223.1-223.7; Korman, A. J. et al. (2007) Adv. Immunol. 90:297-339).Several members of the B7 Superfamily are known, including B7.1 (CD80),B7.2 (CD86), the inducible co-stimulator ligand (ICOS-L), the programmeddeath-1 ligand (PD-L1; B7-H1), the programmed death-2 ligand (PD-L2;B7-DC), B7-H3, B7-H4 and B7-H6 (Collins, M. et al. (2005) Genome Biol.6:223.1-223.7).

The Programmed Death 1 (PD-1) protein is an inhibitory member of theextended CD28/CTLA-4 family of T cell regulators (Okazaki et al. (2002)Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol.170:711-8). Other members of the CD28 family include CD28, CTLA-4, ICOSand BTLA. PD-1 is suggested to exist as a monomer, lacking the unpairedcysteine residue characteristic of other CD28 family members. PD-1 isexpressed on activated B cells, T cells, and monocytes.

The PD-1 gene encodes a 55 kDa type I transmembrane protein (Agata etal. (1996) Int Immunol. 8:765-72). Although structurally similar toCTLA-4, PD-1 lacks the MYPPY motif (SEQ ID NO: 236) that is importantfor B7-1 and B7-2 binding. Two ligands for PD-1 have been identified,PD-L1 (B7-H1) and PD-L2 (B7-DC), that have been shown to downregulate Tcell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med.192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634-43). BothPD-L1 and PD-L2 are B7 homologs that bind to PD-1, but do not bind toother CD28 family members. PD-L1 is abundant in a variety of humancancers (Dong et al. (2002) Nat. Med. 8:787-9).

PD-1 is known as an immunoinhibitory protein that negatively regulatesTCR signals (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. etal. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745). Theinteraction between PD-1 and PD-L1 can act as an immune checkpoint,which can lead to, e.g., a decrease in tumor infiltrating lymphocytes, adecrease in T-cell receptor mediated proliferation, and/or immuneevasion by cancerous cells (Dong et al. (2003) J. Mol. Med. 81:281-7;Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi etal. (2004) Clin. Cancer Res. 10:5094-100). Immune suppression can bereversed by inhibiting the local interaction of PD-1 with PD-L1 orPD-L2; the effect is additive when the interaction of PD-1 with PD-L2 isblocked as well (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66).

Given the importance of immune checkpoint pathways in regulating animmune response, the need exists for developing novel agents thatmodulate the activity of immunoinhibitory proteins, such as PD-1, thusleading to activation of the immune system. Such agents can be used,e.g., for cancer immunotherapy and treatment of other conditions, suchas chronic infection.

SUMMARY

Disclosed herein are antibody molecules (e.g., humanized antibodymolecules) that bind to Programmed Death 1 (PD-1) with high affinity andspecificity. In one embodiment, the anti-PD-1 antibody moleculescomprise a novel combination of framework regions (e.g., FW1, FW2, FW3and/or FW4), e.g., novel combinations of a heavy chain framework regionsand/or light chain framework regions. Nucleic acid molecules encodingthe antibody molecules, expression vectors, host cells and methods formaking the antibody molecules are also provided. Immunoconjugates,multi- or bispecific antibody molecules and pharmaceutical compositionscomprising the antibody molecules are also provided. The anti-PD-1antibody molecules disclosed herein can be used (alone or in combinationwith other agents or therapeutic modalities) to treat, prevent and/ordiagnose disorders, such as cancerous disorders (e.g., solid andsoft-tissue tumors), as well as infectious diseases (e.g., chronicinfectious disorders or sepsis). Thus, compositions and methods fordetecting PD-1, as well as methods for treating various disordersincluding cancer and/or infectious diseases, using the anti-PD-1antibody molecules are disclosed herein.

Accordingly, in one aspect, the invention features an antibody molecule(e.g., an isolated or recombinant antibody molecule) having one or moreof the following properties:

(i) binds to PD-1, e.g., human PD-1, with high affinity, e.g., with anaffinity constant of at least about 10⁷ M⁻¹, typically about 10⁸ M⁻¹,and more typically, about 10⁹ M⁻¹ to 10¹⁰ M⁻¹ or stronger;

(ii) does not substantially bind to CD28, CTLA-4, ICOS or BTLA;

(iii) inhibits or reduces binding of PD-1 to a PD-1 ligand, e.g., PD-L1or PD-L2, or both;

(iv) binds specifically to an epitope on PD-1, e.g., the same or similarepitope as the epitope recognized by murine monoclonal antibody BAP049or a chimeric antibody BAP049, e.g., BAP049-chi or BAP049-chi-Y;

(v) shows the same or similar binding affinity or specificity, or both,as any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09,BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14,BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E;

(vi) shows the same or similar binding affinity or specificity, or both,as an antibody molecule (e.g., an heavy chain variable region and lightchain variable region) described in Table 1;

(vii) shows the same or similar binding affinity or specificity, orboth, as an antibody molecule (e.g., an heavy chain variable region andlight chain variable region) having an amino acid sequence shown inTable 1;

(viii) shows the same or similar binding affinity or specificity, orboth, as an antibody molecule (e.g., an heavy chain variable region andlight chain variable region) encoded by the nucleotide sequence shown inTable 1;

(ix) inhibits, e.g., competitively inhibits, the binding of a secondantibody molecule to PD-1, wherein the second antibody molecule is anantibody molecule described herein, e.g., an antibody molecule chosenfrom, e.g., any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E;

(x) binds the same or an overlapping epitope with a second antibodymolecule to PD-1, wherein the second antibody molecule is an antibodymolecule described herein, e.g., an antibody molecule chosen from, e.g.,any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09,BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14,BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E;

(xi) competes for binding, and/or binds the same epitope, with a secondantibody molecule to PD-1, wherein the second antibody molecule is anantibody molecule described herein, e.g., an antibody molecule chosenfrom, e.g., any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E;

(xii) has one or more biological properties of an antibody moleculedescribed herein, e.g., an antibody molecule chosen from, e.g., any ofBAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05,BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10,BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15,BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E;

(xiii) has one or more pharmacokinetic properties of an antibodymolecule described herein, e.g., an antibody molecule chosen from, e.g.,any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09,BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14,BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E;

(xiv) inhibits one or more activities of PD-1, e.g., results in one ormore of: an increase in tumor infiltrating lymphocytes, an increase inT-cell receptor mediated proliferation, or a decrease in immune evasionby cancerous cells;

(xv) binds human PD-1 and is cross-reactive with cynomolgus PD-1;

(xvi) binds to one or more residues within the C strand, CC′ loop, C′strand, or FG loop of PD-1, or a combination two, three or all of the Cstrand, CC′ loop, C′ strand or FG loop of PD-1, e.g., wherein thebinding is assayed using ELISA or Biacore; or

(xvii) has a VL region that contributes more to binding to PD-1 than aVH region.

In some embodiments, the antibody molecule binds to PD-1 with highaffinity, e.g., with a K_(D) that is about the same, or at least about10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% higher or lower than theK_(D) of a murine or chimeric anti-PD-1 antibody molecule, e.g., amurine or chimeric anti-PD-1 antibody molecule described herein. In someembodiments, the K_(D) of the murine or chimeric anti-PD-1 antibodymolecule is less than about 0.4, 0.3, 0.2, 0.1, or 0.05 nM, e.g.,measured by a Biacore method. In some embodiments, the K_(D) of themurine or chimeric anti-PD-1 antibody molecule is less than about 0.2nM, e.g., about 0.135 nM. In other embodiments, the K_(D) of the murineor chimeric anti PD-1 antibody molecule is less than about 10, 5, 3, 2,or 1 nM, e.g., measured by binding on cells expressing PD-1 (e.g.,300.19 cells). In some embodiments, the K_(D) of the murine or chimericanti PD-1 antibody molecule is less than about 5 nM, e.g., about 4.60 nM(or about 0.69 μg/mL).

In some embodiments, the anti-PD-1 antibody molecule binds to PD-1 witha K_(off) slower than 1×10⁻⁴, 5×10⁻⁵, or 1×10⁻⁵ s⁻¹, e.g., about1.65×10⁻⁵ s⁻¹. In some embodiments, the anti-PD-1 antibody moleculebinds to PD-1 with a K_(on) faster than 1×10⁴, 5×10⁴, 1×10⁵, or 5×10⁵M⁻¹s⁻¹, e.g., about 1.23×10⁵ M⁻¹s⁻¹.

In some embodiments, the expression level of the antibody molecule ishigher, e.g., at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10-foldhigher, than the expression level of a murine or chimeric antibodymolecule, e.g., a murine or chimeric anti-PD-1 antibody moleculedescribed herein. In some embodiments, the antibody molecule isexpressed in CHO cells.

In some embodiments, the anti-PD-1 antibody molecule reduces one or morePD-1-associated activities with an IC₅₀ (concentration at 50%inhibition) that is about the same or lower, e.g., at least about 10%,20%, 30%, 40%, 50%, 60%, 70%, 80% or 90% lower, than the IC₅₀ of amurine or chimeric anti-PD-1 antibody molecule, e.g., a murine orchimeric anti-PD-1 antibody molecule described herein. In someembodiments, the IC₅₀ of the murine or chimeric anti-PD-1 antibodymolecule is less than about 6, 5, 4, 3, 2, or 1 nM, e.g., measured bybinding on cells expressing PD-1 (e.g., 300.19 cells). In someembodiments, the IC₅₀ of the murine or chimeric anti-PD-1 antibodymolecule is less than about 4 nM, e.g., about 3.40 nM (or about 0.51μg/mL). In some embodiments, the PD-1-associated activity reduced is thebinding of PD-L1 and/or PD-L2 to PD-1. In some embodiments, theanti-PD-1 antibody molecule binds to peripheral blood mononucleatedcells (PBMCs) activated by Staphylococcal enterotoxin B (SEB). In otherembodiments, the anti-PD-1 antibody molecule increases the expression ofIL-2 on whole blood activated by SEB. For example, the anti-PD-1antibody increases the expression of IL-2 by at least about 2, 3, 4, or5-fold, compared to the expression of IL-2 when an isotype control(e.g., IgG4) is used.

In some embodiments, the anti-PD-1 antibody molecule has improvedstability, e.g., at least about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9 or10-fold more stable in vivo or in vitro, than a murine or chimericanti-PD-1 antibody molecule, e.g., a murine or chimeric anti-PD-1antibody molecule described herein.

In one embodiment, the anti PD-1 antibody molecule is a humanizedantibody molecule and has a risk score based on T cell epitope analysisof 300 to 700, 400 to 650, 450 to 600, or a risk score as describedherein.

In another embodiment, the anti-PD-1 antibody molecule comprises atleast one antigen-binding region, e.g., a variable region or anantigen-binding fragment thereof, from an antibody described herein,e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences.

In yet another embodiment, the anti-PD-1 antibody molecule comprises atleast one, two, three or four variable regions from an antibodydescribed herein, e.g., an antibody chosen from any of BAP049-hum01,BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, orBAP049-Clone-E; or as described in Table 1, or encoded by the nucleotidesequence in Table 1; or a sequence substantially identical (e.g., atleast 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to anyof the aforesaid sequences.

In yet another embodiment, the anti-PD-1 antibody molecule comprises atleast one or two heavy chain variable regions from an antibody describedherein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences.

In yet another embodiment, the anti-PD-1 antibody molecule comprises atleast one or two light chain variable regions from an antibody describedherein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences.

In yet another embodiment, the anti-PD-1 antibody molecule includes aheavy chain constant region for an IgG4, e.g., a human IgG4. In oneembodiment, the human IgG4 includes a substitution at position 228according to EU numbering (e.g., a Ser to Pro substitution). In stillanother embodiment, the anti-PD-1 antibody molecule includes a heavychain constant region for an IgG1, e.g., a human IgG1. In oneembodiment, the human IgG1 includes a substitution at position 297according to EU numbering (e.g., an Asn to Ala substitution). In oneembodiment, the human IgG1 includes a substitution at position 265according to EU numbering, a substitution at position 329 according toEU numbering, or both (e.g., an Asp to Ala substitution at position 265and/or a Pro to Ala substitution at position 329). In one embodiment,the human IgG1 includes a substitution at position 234 according to EUnumbering, a substitution at position 235 according to EU numbering, orboth (e.g., a Leu to Ala substitution at position 234 and/or a Leu toAla substitution at position 235). In one embodiment, the heavy chainconstant region comprises an amino sequence set forth in Table 3, or asequence substantially identical (e.g., at least 80%, 85%, 90%, 92%,95%, 97%, 98%, 99% or higher identical) thereto.

In yet another embodiment, the anti-PD-1 antibody molecule includes akappa light chain constant region, e.g., a human kappa light chainconstant region. In one embodiment, the light chain constant regioncomprises an amino sequence set forth in Table 3, or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) thereto.

In another embodiment, the anti-PD-1 antibody molecule includes a heavychain constant region for an IgG4, e.g., a human IgG4, and a kappa lightchain constant region, e.g., a human kappa light chain constant region,e.g., a heavy and light chain constant region comprising an aminosequence set forth in Table 3, or a sequence substantially identical(e.g., at least 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higheridentical) thereto. In one embodiment, the human IgG4 includes asubstitution at position 228 according to EU numbering (e.g., a Ser toPro substitution). In yet another embodiment, the anti-PD-1 antibodymolecule includes a heavy chain constant region for an IgG1, e.g., ahuman IgG1, and a kappa light chain constant region, e.g., a human kappalight chain constant region, e.g., a heavy and light chain constantregion comprising an amino sequence set forth in Table 3, or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) thereto. In one embodiment, the human IgG1includes a substitution at position 297 according to EU numbering (e.g.,an Asn to Ala substitution). In one embodiment, the human IgG1 includesa substitution at position 265 according to EU numbering, a substitutionat position 329 according to EU numbering, or both (e.g., an Asp to Alasubstitution at position 265 and/or a Pro to Ala substitution atposition 329). In one embodiment, the human IgG1 includes a substitutionat position 234 according to EU numbering, a substitution at position235 according to EU numbering, or both (e.g., a Leu to Ala substitutionat position 234 and/or a Leu to Ala substitution at position 235).

In another embodiment, the anti-PD-1 antibody molecule includes a heavychain variable domain and a constant region, a light chain variabledomain and a constant region, or both, comprising the amino acidsequence of BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1, orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequences. Theanti-PD-1 antibody molecule, optionally, comprises a leader sequencefrom a heavy chain, a light chain, or both, as shown in Table 4; or asequence substantially identical thereto.

In yet another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, or three complementarity determining regions (CDRs) froma heavy chain variable region of an antibody described herein, e.g., anantibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences.

In yet another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, or three CDRs (or collectively all of the CDRs) from aheavy chain variable region comprising an amino acid sequence shown inTable 1, or encoded by a nucleotide sequence shown in Table 1. In oneembodiment, one or more of the CDRs (or collectively all of the CDRs)have one, two, three, four, five, six or more changes, e.g., amino acidsubstitutions or deletions, relative to the amino acid sequence shown inTable 1, or encoded by a nucleotide sequence shown in Table 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, or three CDRs from a light chain variable region of anantibody described herein, e.g., an antibody chosen from any ofBAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05,BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10,BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15,BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1, orencoded by the nucleotide sequence in Table 1; or a sequencesubstantially identical (e.g., at least 80%, 85%, 90%, 92%, 95%, 97%,98%, 99% or higher identical) to any of the aforesaid sequence.

In yet another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, or three CDRs (or collectively all of the CDRs) from alight chain variable region comprising an amino acid sequence shown inTable 1, or encoded by a nucleotide sequence shown in Table 1. In oneembodiment, one or more of the CDRs (or collectively all of the CDRs)have one, two, three, four, five, six or more changes, e.g., amino acidsubstitutions or deletions, relative to the amino acid sequence shown inTable 1, or encoded by a nucleotide sequence shown in Table 1. Incertain embodiments, the anti-PD-1 antibody molecule includes asubstitution in a light chain CDR, e.g., one or more substitutions in aCDR1, CDR2 and/or CDR3 of the light chain. In one embodiment, theanti-PD-1 antibody molecule includes a substitution in the light chainCDR3 at position 102 of the light variable region, e.g., a substitutionof a cysteine to tyrosine, or a cysteine to serine residue, at position102 of the light variable region according to Table 1 (e.g., SEQ ID NO:16 or 24 for murine or chimeric, unmodified; or any of SEQ ID NOs: 34,42, 46, 54, 58, 62, 66, 70, 74, or 78 for a modified sequence).

In another embodiment, the anti-PD-1 antibody molecule includes at leastone, two, three, four, five or six CDRs (or collectively all of theCDRs) from a heavy and light chain variable region comprising an aminoacid sequence shown in Table 1, or encoded by a nucleotide sequenceshown in Table 1. In one embodiment, one or more of the CDRs (orcollectively all of the CDRs) have one, two, three, four, five, six ormore changes, e.g., amino acid substitutions or deletions, relative tothe amino acid sequence shown in Table 1, or encoded by a nucleotidesequence shown in Table 1.

In one embodiment, the anti-PD-1 antibody molecule includes all six CDRsfrom an antibody described herein, e.g., an antibody chosen from any ofBAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05,BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10,BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15,BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E; or as described in Table 1, orencoded by the nucleotide sequence in Table 1, or closely related CDRs,e.g., CDRs which are identical or which have at least one amino acidalteration, but not more than two, three or four alterations (e.g.,substitutions, deletions, or insertions, e.g., conservativesubstitutions). In one embodiment, the anti-PD-1 antibody molecule mayinclude any CDR described herein. In certain embodiments, the anti-PD-1antibody molecule includes a substitution in a light chain CDR, e.g.,one or more substitutions in a CDR1, CDR2 and/or CDR3 of the lightchain. In one embodiment, the anti-PD-1 antibody molecule includes asubstitution in the light chain CDR3 at position 102 of the lightvariable region, e.g., a substitution of a cysteine to tyrosine, or acysteine to serine residue, at position 102 of the light variable regionaccording to Table 1 (e.g., SEQ ID NO: 16 or 24 for murine or chimeric,unmodified; or any of SEQ ID NOs: 34, 42, 46, 54, 58, 62, 66, 70, 74, or78 for a modified sequence).

In another embodiment, the anti-PD-1 antibody molecule includes at leastone, two, or three CDRs according to Kabat et al. (e.g., at least one,two, or three CDRs according to the Kabat definition as set out inTable 1) from a heavy chain variable region of an antibody describedherein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences; or which have at least one amino acid alteration, but notmore than two, three or four alterations (e.g., substitutions,deletions, or insertions, e.g., conservative substitutions) relative toone, two, or three CDRs according to Kabat et al. shown in Table 1.

In another embodiment, the anti-PD-1 antibody molecule includes at leastone, two, or three CDRs according to Kabat et al. (e.g., at least one,two, or three CDRs according to the Kabat definition as set out inTable 1) from a light chain variable region of an antibody describedherein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences; or which have at least one amino acid alteration, but notmore than two, three or four alterations (e.g., substitutions,deletions, or insertions, e.g., conservative substitutions) relative toone, two, or three CDRs according to Kabat et al. shown in Table 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, three, four, five, or six CDRs according to Kabat et al.(e.g., at least one, two, three, four, five, or six CDRs according tothe Kabat definition as set out in Table 1) from the heavy and lightchain variable regions of an antibody described herein, e.g., anantibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences; or which have at least one amino acid alteration, but notmore than two, three or four alterations (e.g., substitutions,deletions, or insertions, e.g., conservative substitutions) relative toone, two, three, four, five, or six CDRs according to Kabat et al. shownin Table 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes allsix CDRs according to Kabat et al. (e.g., all six CDRs according to theKabat definition as set out in Table 1) from the heavy and light chainvariable regions of an antibody described herein, e.g., an antibodychosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or a sequence substantially identical (e.g., at least 80%, 85%, 90%,92%, 95%, 97%, 98%, 99% or higher identical) to any of the aforesaidsequences; or which have at least one amino acid alteration, but notmore than two, three or four alterations (e.g., substitutions,deletions, or insertions, e.g., conservative substitutions) relative toall six CDRs according to Kabat et al. shown in Table 1. In oneembodiment, the anti-PD-1 antibody molecule may include any CDRdescribed herein.

In another embodiment, the anti-PD-1 antibody molecule includes at leastone, two, or three Chothia hypervariable loops (e.g., at least one, two,or three hypervariable loops according to the Chothia definition as setout in Table 1) from a heavy chain variable region of an antibodydescribed herein, e.g., an antibody chosen from any of BAP049-hum01,BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, orBAP049-Clone-E; or as described in Table 1, or encoded by the nucleotidesequence in Table 1; or at least the amino acids from thosehypervariable loops that contact PD-1; or which have at least one aminoacid alteration, but not more than two, three or four alterations (e.g.,substitutions, deletions, or insertions, e.g., conservativesubstitutions) relative to one, two, or three hypervariable loopsaccording to Chothia et al. shown in Table 1.

In another embodiment, the anti-PD-1 antibody molecule includes at leastone, two, or three Chothia hypervariable loops (e.g., at least one, two,or three hypervairalbe loops according to the Chothia definition as setout in Table 1) of a light chain variable region of an antibodydescribed herein, e.g., an antibody chosen from any of BAP049-hum01,BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, orBAP049-Clone-E; or as described in Table 1, or encoded by the nucleotidesequence in Table 1; or at least the amino acids from thosehypervariable loops that contact PD-1; or which have at least one aminoacid alteration, but not more than two, three or four alterations (e.g.,substitutions, deletions, or insertions, e.g., conservativesubstitutions) relative to one, two, or three hypervariable loopsaccording to Chothia et al. shown in Table 1.

In yet another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, three, four, five, or six hypervariable loops (e.g., atleast one, two, three, four, five, or six hypervariable loops accordingto the Chothia definition as set out in Table 1) from the heavy andlight chain variable regions of an antibody described herein, e.g., anantibody chosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1, or encoded by the nucleotide sequence in Table 1;or at least the amino acids from those hypervariable loops that contactPD-1; or which have at least one amino acid alteration, but not morethan two, three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions) relative to one, two,three, four, five or six hypervariable loops according to Chothia et al.shown in Table 1.

In one embodiment, the anti-PD-1 antibody molecule includes all sixhypervariable loops (e.g., all six hypervariable loops according to theChothia definition as set out in Table 1) of an antibody describedherein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E, orclosely related hypervariable loops, e.g., hypervariable loops which areidentical or which have at least one amino acid alteration, but not morethan two, three or four alterations (e.g., substitutions, deletions, orinsertions, e.g., conservative substitutions); or which have at leastone amino acid alteration, but not more than two, three or fouralterations (e.g., substitutions, deletions, or insertions, e.g.,conservative substitutions) relative to all six hypervariable loopsaccording to Chothia et al. shown in Table 1. In one embodiment, theanti-PD-1 antibody molecule may include any hypervariable loop describedherein.

In still another embodiment, the anti-PD-1 antibody molecule includes atleast one, two, or three hypervariable loops that have the samecanonical structures as the corresponding hypervariable loop of anantibody described herein, e.g., an antibody chosen from any ofBAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05,BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10,BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15,BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E, e.g., the same canonical structuresas at least loop 1 and/or loop 2 of the heavy and/or light chainvariable domains of an antibody described herein. See, e.g., Chothia etal., (1992) J. Mol. Biol. 227:799-817; Tomlinson et al., (1992) J. Mol.Biol. 227:776-798 for descriptions of hypervariable loop canonicalstructures. These structures can be determined by inspection of thetables described in these references.

In certain embodiments, the anti-PD-1 antibody molecule includes acombination of CDRs or hypervariable loops defined according to theKabat et al. and Chothia et al.

In one embodiment, the anti-PD-1 antibody molecule includes at leastone, two or three CDRs or hypervariable loops from a heavy chainvariable region of an antibody described herein, e.g., an antibodychosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E,according to the Kabat and Chothia definition (e.g., at least one, two,or three CDRs or hypervariable loops according to the Kabat and Chothiadefinition as set out in Table 1); or encoded by the nucleotide sequencein Table 1; or a sequence substantially identical (e.g., at least 80%,85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical) to any of theaforesaid sequences; or which have at least one amino acid alteration,but not more than two, three or four alterations (e.g., substitutions,deletions, or insertions, e.g., conservative substitutions) relative toone, two, or three CDRs or hypervariable loops according to Kabat and/orChothia shown in Table 1.

For example, the anti-PD-1 antibody molecule can include VH CDR1according to Kabat et al. or VH hypervariable loop 1 according toChothia et al., or a combination thereof, e.g., as shown in Table 1. Inone embodiment, the combination of Kabat and Chothia CDR of VH CDR1comprises the amino acid sequence GYTFTTYWMH (SEQ ID NO: 224), or anamino acid sequence substantially identical thereto (e.g., having atleast one amino acid alteration, but not more than two, three or fouralterations (e.g., substitutions, deletions, or insertions, e.g.,conservative substitutions)). The anti-PD-1 antibody molecule canfurther include, e.g., VH CDRs 2-3 according to Kabat et al. and VL CDRs1-3 according to Kabat et al., e.g., as shown in Table 1. Accordingly,in some embodiments, framework regions are defined based on acombination of CDRs defined according to Kabat et al. and hypervariableloops defined according to Chothia et al. For example, the anti-PD-1antibody molecule can include VH FR1 defined based on VH hypervariableloop 1 according to Chothia et al. and VH FR2 defined based on VH CDRs1-2 according to Kabat et al., e.g., as shown in Table 1. The anti-PD-1antibody molecule can further include, e.g., VH FRs 3-4 defined based onVH CDRs 2-3 according to Kabat et al. and VL FRs 1-4 defined based on VLCDRs 1-3 according to Kabat et al.

The anti-PD-1 antibody molecule can contain any combination of CDRs orhypervariable loops according to the Kabat and Chothia definitions. Inone embodiment, the anti-PD-1 antibody molecule includes at least one,two or three CDRs from a light chain variable region of an antibodydescribed herein, e.g., an antibody chosen from any of BAP049-hum01,BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, orBAP049-Clone-E, according to the Kabat and Chothia definition (e.g., atleast one, two, or three CDRs according to the Kabat and Chothiadefinition as set out in Table 1).

In an embodiment, e.g., an embodiment comprising a variable region, aCDR (e.g., Chothia CDR or Kabat CDR), or other sequence referred toherein, e.g., in Table 1, the antibody molecule is a monospecificantibody molecule, a bispecific antibody molecule, or is an antibodymolecule that comprises an antigen binding fragment of an antibody,e.g., a half antibody or antigen binding fragment of a half antibody. Incertain embodiments the antibody molecule is a bispecific antibodymolecule having a first binding specificity for PD-1 and a secondbinding specificity for TIM-3, LAG-3, CEACAM (e.g., CEACAM-1 and/orCEACAM-5), PD-L1 or PD-L2.

In one embodiment, the anti-PD-1 antibody molecule includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5,and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chainvariable region (VL) comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 33;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO:1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32;

(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or

(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; aVHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

In one embodiment, the anti-PD-1 antibody molecule comprises a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 aminoacid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO:13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 aminoacid sequence of SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule comprises a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 aminoacid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO:10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 aminoacid sequence of SEQ ID NO: 32.

In one embodiment, the anti-PD-1 antibody molecule comprises a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule comprises a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO: 32.

In one embodiment, the antibody molecule is a humanized antibodymolecule. In another embodiment, the antibody molecule is a monospecificantibody molecule. In yet another embodiment, the antibody molecule is abispecific antibody molecule.

In one embodiment, the anti-PD-1 antibody molecule includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; aVHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

In another embodiment, the anti-PD-1 antibody molecule includes:

(i) a heavy chain variable region (VH) including a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) including a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule comprises the VHCDR1amino acid sequence of SEQ ID NO: 1. In another embodiment, theanti-PD-1 antibody molecule comprises the VHCDR1 amino acid sequence ofSEQ ID NO: 4. In yet another embodiment, the anti-PD-1 antibody moleculecomprises the VHCDR1 amino acid sequence of SEQ ID NO: 224.

In one embodiment, the light or the heavy chain variable framework(e.g., the region encompassing at least FR1, FR2, FR3, and optionallyFR4) of the anti-PD-1 antibody molecule can be chosen from: (a) a lightor heavy chain variable framework including at least 80%, 85%, 87% 90%,92%, 93%, 95%, 97%, 98%, or preferably 100% of the amino acid residuesfrom a human light or heavy chain variable framework, e.g., a light orheavy chain variable framework residue from a human mature antibody, ahuman germline sequence, or a human consensus sequence; (b) a light orheavy chain variable framework including from 20% to 80%, 40% to 60%,60% to 90%, or 70% to 95% of the amino acid residues from a human lightor heavy chain variable framework, e.g., a light or heavy chain variableframework residue from a human mature antibody, a human germlinesequence, or a human consensus sequence; (c) a non-human framework(e.g., a rodent framework); or (d) a non-human framework that has beenmodified, e.g., to remove antigenic or cytotoxic determinants, e.g.,deimmunized, or partially humanized. In one embodiment, the light orheavy chain variable framework region (particularly FR1, FR2 and/or FR3)includes a light or heavy chain variable framework sequence at least 70,75, 80, 85, 87, 88, 90, 92, 94, 95, 96, 97, 98, 99% identical oridentical to the frameworks of a VL or VH segment of a human germlinegene.

In certain embodiments, the anti-PD-1 antibody molecule comprises aheavy chain variable domain having at least one, two, three, four, five,six, seven, ten, fifteen, twenty or more changes, e.g., amino acidsubstitutions or deletions, from an amino acid sequence ofBAP049-chi-HC, e.g., the amino acid sequence of the FR region in theentire variable region, e.g., shown in FIGS. 9A-9B, or SEQ ID NO: 18,20, 22 or 30. In one embodiment, the anti-PD-1 antibody moleculecomprises a heavy chain variable domain having one or more of: E atposition 1, V at position 5, A at position 9, V at position 11, K atposition 12, K at position 13, E at position 16, L at position 18, R atposition 19, I or V at position 20, G at position 24, I at position 37,A or S at position 40, T at position 41, S at position 42, R at position43, M or L at position 48, V or F at position 68, T at position 69, I atposition 70, S at position 71, A or R at position 72, K or N at position74, T or K at position 76, S or N at position 77, L at position 79, L atposition 81, E or Q at position 82, M at position 83, S or N at position84, R at position 87, A at position 88, or T at position 91 of aminoacid sequence of BAP049-chi-HC, e.g., the amino acid sequence of the FRin the entire variable region, e.g., shown in FIGS. 9A-9B, or SEQ ID NO:18, 20, 22 or 30.

Alternatively, or in combination with the heavy chain substitutions ofBAP049-chi-HC described herein, the anti-PD-1 antibody moleculecomprises a light chain variable domain having at least one, two, three,four, five, six, seven, ten, fifteen, twenty or more amino acid changes,e.g., amino acid substitutions or deletions, from an amino acid sequenceof BAP049-chi-LC, e.g., the amino acid sequence shown in FIGS. 10A-10B,or SEQ ID NO: 24 or 26. In one embodiment, the anti-PD-1 antibodymolecule comprises a heavy chain variable domain having one or more of:E at position 1, V at position 2, Q at position 3, L at position 4, T atposition 7, D or L or A at position 9, F or T at position 10, Q atposition 11, S or P at position 12, L or A at position 13, S at position14, P or L or V at position 15, K at position 16, Q or D at position 17,R at position 18, A at position 19, S at position 20, I or L at position21, T at position 22, L at position 43, K at position 48, A or S atposition 49, R or Q at position 51, Y at position 55, I at position 64,S or P at position 66, S at position 69, Y at position 73, G at position74, E at position 76, F at position 79, N at position 82, N at position83, L or I at position 84, E at position 85, S or P at position 86, D atposition 87, A or F or I at position 89, T or Y at position 91, F atposition 93, or Y at position 102 of the amino acid sequence ofBAP049-chi-LC, e.g., the amino acid sequence shown in FIGS. 10A-10B, orSEQ ID NO: 24 or 26.

In other embodiments, the anti-PD-1 antibody molecule includes one, two,three, or four heavy chain framework regions (e.g., a VHFW amino acidsequence shown in Table 2, or encoded by the nucleotide sequence shownin Table 2), or a sequence substantially identical thereto.

In yet other embodiments, the anti-PD-1 antibody molecule includes one,two, three, or four light chain framework regions (e.g., a VLFW aminoacid sequence shown in Table 2, or encoded by the nucleotide sequenceshown in Table 2), or a sequence substantially identical thereto.

In other embodiments, the anti-PD-1 antibody molecule includes one, two,three, or four heavy chain framework regions (e.g., a VHFW amino acidsequence shown in Table 2, or encoded by the nucleotide sequence shownin Table 2), or a sequence substantially identical thereto; and one,two, three, or four light chain framework regions (e.g., a VLFW aminoacid sequence shown in Table 2, or encoded by the nucleotide sequenceshown in Table 2), or a sequence substantially identical thereto.

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework region 1 (VHFW1) of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E (e.g.,SEQ ID NO: 147). In some embodiments, the antibody molecule comprisesthe heavy chain framework region 1 (VHFW1) of BAP049-hum14 orBAP049-hum15 (e.g., SEQ ID NO: 151).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework region 2 (VHFW2) of BAP049-hum01, BAP049-hum02,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum09, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, or BAP049-Clone-E (e.g., SEQ ID NO: 153). In someembodiments, the antibody molecule comprises the heavy chain frameworkregion 2 (VHFW2) of BAP049-hum03, BAP049-hum04, BAP049-hum08,BAP049-hum10, BAP049-hum14, BAP049-hum15, or BAP049-Clone-D (e.g., SEQID NO: 157). In some embodiments, the antibody molecule comprises theheavy chain framework region 2 (VHFW2) of BAP049-hum16 (e.g., SEQ ID NO:160).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework region 3 (VHFW3) of BAP049-hum01, BAP049-hum02,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum09, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, or BAP049-Clone-E (e.g., SEQ ID NO: 162). In someembodiments, the antibody molecule comprises the heavy chain frameworkregion 3 (VHFW3) of BAP049-hum03, BAP049-hum04, BAP049-hum08,BAP049-hum10, BAP049-hum14, BAP049-hum15, BAP049-hum16, orBAP049-Clone-D (e.g., SEQ ID NO: 166).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework region 4 (VHFW4) of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E (e.g.,SEQ ID NO: 169).

In some embodiments, the anti-PD-1 antibody molecule comprises the lightchain framework region 1 (VLFW1) of BAP049-hum08, BAP049-hum09,BAP049-hum15, BAP049-hum16, or BAP049-Clone-C (e.g., SEQ ID NO: 174). Insome embodiments, the antibody molecule comprises the light chainframework region 1 (VLFW1) of BAP049-hum01, BAP049-hum04, BAP049-hum05,BAP049-hum07, BAP049-hum10, BAP049-hum11, BAP049-hum14, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-D, or BAP049-Clone-E (e.g., SEQ ID NO:177). In some embodiments, the antibody molecule comprises the lightchain framework region 1 (VLFW1) of BAP049-hum06 (e.g., SEQ ID NO: 181).In some embodiments, the antibody molecule comprises the light chainframework region 1 (VLFW1) of BAP049-hum13 (e.g., SEQ ID NO: 183). Insome embodiments, the antibody molecule comprises the light chainframework region 1 (VLFW1) of BAP049-hum02, BAP049-hum03, orBAP049-hum12 (e.g., SEQ ID NO: 185).

In some embodiments, the anti-PD-1 antibody molecule comprises the lightchain framework region 2 (VLFW2) of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum06, BAP049-hum08, BAP049-hum09, BAP049-hum10,BAP049-hum11, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-D, or BAP049-Clone-E (e.g., SEQ ID NO:187). In some embodiments, the antibody molecule comprises the lightchain framework region 2 (VLFW2) of BAP049-hum04, BAP049-hum05,BAP049-hum07, BAP049-hum13, or BAP049-Clone-C (e.g., SEQ ID NO: 191). Insome embodiments, the antibody molecule comprises the light chainframework region 2 (VLFW2) of BAP049-hum12 (e.g., SEQ ID NO: 194).

In some embodiments, the anti-PD-1 antibody molecule comprises the lightchain framework region 3 (VLFW3) of BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E (e.g., SEQ ID NO: 196). In someembodiments, the antibody molecule comprises the light chain frameworkregion 3 (VLFW3) of BAP049-hum02 or BAP049-hum03 (e.g., SEQ ID NO: 200).

In some embodiments, the antibody molecule comprises the light chainframework region 3 (VLFW3) of BAP049-hum01 or BAP049-Clone-A (e.g., SEQID NO: 202). In some embodiments, the antibody molecule comprises thelight chain framework region 3 (VLFW3) of BAP049-hum04, BAP049-hum05, orBAP049-Clone-B (e.g., SEQ ID NO: 205).

In some embodiments, the anti-PD-1 antibody molecule comprises the lightchain framework region 4 (VLFW4) of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E (e.g.,SEQ ID NO: 208).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum01, BAP049-hum02, BAP049-hum05,BAP049-hum06, BAP-hum07, BAP049-hum09, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, orBAP049-Clone-E (e.g., SEQ ID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2),and SEQ ID NO: 162 (VHFW3)). In some embodiments, the antibody moleculecomprises the heavy chain framework regions 1-3 of BAP049-hum03,BAP049-hum04, BAP049-hum08, BAP049-hum10, or BAP049-Clone-D (e.g., SEQID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)).In some embodiments, the antibody molecule comprises the heavy chainframework regions 1-3 of BAP049-hum14 or BAP049-hum15 (e.g., SEQ ID NO:151 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)). Insome embodiments, the antibody molecule comprises the heavy chainframework regions 1-3 of BAP049-hum16 (e.g., SEQ ID NO: 147 (VHFW1), SEQID NO: 160 (VHFW2), and SEQ ID NO: 166 (VHFW3)). In some embodiments,the antibody molecule further comprises the heavy chain framework region4 (VHFW4) of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09,BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14,BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E (e.g., SEQ ID NO:169).

In some embodiments, the anti-PD-1 antibody molecule comprises the lightchain framework regions 1-3 of BAP049-hum01 or BAP049-Clone-A (e.g., SEQID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 202 (VLFW3)).In some embodiments, the antibody molecule comprises the light chainframework regions 1-3 of BAP049-hum02 or BAP049-hum03 (e.g., SEQ ID NO:185 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 200 (VLFW3)). Insome embodiments, the antibody molecule comprises the light chainframework regions 1-3 of BAP049-hum04, BAP049-hum05, or BAP049-Clone-B(e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO:205 (VLFW3)). In some embodiments, the antibody molecule comprises thelight chain framework regions 1-3 of BAP049-hum06 (e.g., SEQ ID NO: 181(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In someembodiments, the antibody molecule comprises the light chain frameworkregions 1-3 of BAP049-hum07 (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO:191 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In some embodiments, theantibody molecule comprises the light chain framework regions 1-3 ofBAP049-hum08, BAP049-hum09, BAP049-hum15, BAP049-hum16, orBAP049-Clone-C (e.g., SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2),and SEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody moleculecomprises the light chain framework regions 1-3 of BAP049-hum10,BAP049-hum11, BAP049-hum14, BAP049-Clone-D, or BAP049-Clone-E (e.g., SEQID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).In some embodiments, the antibody molecule comprises the light chainframework regions 1-3 of BAP049-hum12 (e.g., SEQ ID NO: 185 (VLFW1), SEQID NO: 194 (VLFW2), and SEQ ID NO: 196 (VLFW3)). In some embodiments,the antibody molecule comprises the light chain framework regions 1-3 ofBAP049-hum13 (e.g., SEQ ID NO: 183 (VLFW1), SEQ ID NO: 191 (VLFW2), andSEQ ID NO: 196 (VLFW3)). In some embodiments, the antibody moleculefurther comprises the light chain framework region 4 (VLFW4) ofBAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05,BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10,BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15,BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C,BAP049-Clone-D, or BAP049-Clone-E (e.g., SEQ ID NO: 208).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum01 or BAP049-Clone-A (e.g., SEQID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3))and the light chain framework regions 1-3 of BAP049-hum01 orBAP049-Clone-A (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2),and SEQ ID NO: 202 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum02 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum02 (e.g., SEQ ID NO: 185(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 200 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum03 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum03 (e.g., SEQ ID NO: 185(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 200 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum04 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum04 (e.g., SEQ ID NO: 177(VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 205 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum05 or BAP049-Clone-B (e.g., SEQID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3))and the light chain framework regions 1-3 of BAP049-hum05 orBAP049-Clone-B (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 191 (VLFW2),and SEQ ID NO: 205 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum06 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum06 (e.g., SEQ ID NO: 181(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum07 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum07 (e.g., SEQ ID NO: 177(VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum08 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum08 (e.g., SEQ ID NO: 174(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum09 or BAP049-Clone-C (e.g., SEQID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3))and the light chain framework regions 1-3 of BAP049-hum09 orBAP049-Clone-C (e.g., SEQ ID NO: 174 (VLFW1), SEQ ID NO: 187 (VLFW2),and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum10 or BAP049-Clone-D (e.g., SEQID NO: 147 (VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3))and the light chain framework regions 1-3 of BAP049-hum10 orBAP049-Clone-D (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2),and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum11 or BAP049-Clone-E (e.g., SEQID NO: 147 (VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3))and the light chain framework regions 1-3 of BAP049-hum11 orBAP049-Clone-E (e.g., SEQ ID NO: 177 (VLFW1), SEQ ID NO: 187 (VLFW2),and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum12 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum12 (e.g., SEQ ID NO: 185(VLFW1), SEQ ID NO: 194 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum13 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 153 (VHFW2), and SEQ ID NO: 162 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum13 (e.g., SEQ ID NO: 183(VLFW1), SEQ ID NO: 191 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum14 (e.g., SEQ ID NO: 151(VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum14 (e.g., SEQ ID NO: 177(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum15 (e.g., SEQ ID NO: 151(VHFW1), SEQ ID NO: 157 (VHFW2), and SEQ ID NO: 166 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum15 (e.g., SEQ ID NO: 174(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule comprises the heavychain framework regions 1-3 of BAP049-hum16 (e.g., SEQ ID NO: 147(VHFW1), SEQ ID NO: 160 (VHFW2), and SEQ ID NO: 166 (VHFW3)) and thelight chain framework regions 1-3 of BAP049-hum16 (e.g., SEQ ID NO: 174(VLFW1), SEQ ID NO: 187 (VLFW2), and SEQ ID NO: 196 (VLFW3)).

In some embodiments, the anti-PD-1 antibody molecule further comprisesthe heavy chain framework region 4 (VHFW4) of BAP049-hum01,BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, orBAP049-Clone-E (e.g., SEQ ID NO: 169) and the light chain frameworkregion 4 (VLFW4) of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E (e.g.,SEQ ID NO: 208).

In some embodiments, the anti-PD-1 antibody molecule comprises a heavychain framework region having a combination of framework regions FW1,FW2 and FW3 as shown in FIG. 5 or 7. In other embodiment, the antibodymolecule comprises a light chain framework region having a combinationof framework regions FW1, FW2 and FW3 as shown in FIG. 5 or 7. In yetother embodiments, the antibody molecule comprises a heavy chainframework region having a combination of framework regions FW1, FW2 andFW3 as shown in FIG. 5 or 7, and a light chain framework region having acombination of framework regions FW1, FW2 and FW3 as shown in FIG. 5 or7.

In one embodiment, the heavy or light chain variable domain, or both, ofthe anti-PD-1 antibody molecule includes an amino acid sequence, whichis substantially identical to an amino acid disclosed herein, e.g., atleast 80%, 85%, 90%, 92%, 95%, 97%, 98%, 99% or higher identical to avariable region of an antibody described herein, e.g., an antibodychosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or as described inTable 1, or encoded by the nucleotide sequence in Table 1; or whichdiffers at least 1 or 5 residues, but less than 40, 30, 20, or 10residues, from a variable region of an antibody described herein.

In one embodiment, the heavy or light chain variable region, or both, ofthe anti-PD-1 antibody molecule includes an amino acid sequence encodedby a nucleic acid sequence described herein or a nucleic acid thathybridizes to a nucleic acid sequence described herein (e.g., a nucleicacid sequence as shown in Tables 1 and 2) or its complement, e.g., underlow stringency, medium stringency, or high stringency, or otherhybridization condition described herein.

In another embodiment, the anti-PD-1 antibody molecule comprises atleast one, two, three, or four antigen-binding regions, e.g., variableregions, having an amino acid sequence as set forth in Table 1, or asequence substantially identical thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, or which differs byno more than 1, 2, 5, 10, or 15 amino acid residues from the sequencesshown in Table 1. In another embodiment, the anti-PD-1 antibody moleculeincludes a VH and/or VL domain encoded by a nucleic acid having anucleotide sequence as set forth in Table 1, or a sequence substantiallyidentical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% ormore identical thereto, or which differs by no more than 3, 6, 15, 30,or 45 nucleotides from the sequences shown in Table 1.

In yet another embodiment, the anti-PD-1 antibody molecule comprises atleast one, two, or three CDRs from a heavy chain variable region havingan amino acid sequence as set forth in Table 1, or a sequencesubstantially homologous thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, and/or having one, two, threeor more substitutions, insertions or deletions, e.g., conservedsubstitutions). In yet another embodiment, the anti-PD-1 antibodymolecule comprises at least one, two, or three CDRs from a light chainvariable region having an amino acid sequence as set forth in Table 1,or a sequence substantially homologous thereto (e.g., a sequence atleast about 85%, 90%, 95%, 99% or more identical thereto, and/or havingone, two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions). In yet another embodiment, the anti-PD-1antibody molecule comprises at least one, two, three, four, five or sixCDRs from heavy and light chain variable regions having an amino acidsequence as set forth in Table 1), or a sequence substantiallyhomologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%or more identical thereto, and/or having one, two, three or moresubstitutions, insertions or deletions, e.g., conserved substitutions).

In one embodiment, the anti-PD-1 antibody molecule comprises at leastone, two, or three CDRs and/or hypervariable loops from a heavy chainvariable region having an amino acid sequence of an antibody describedherein, e.g., an antibody chosen from any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E, assummarized in Table 1, or a sequence substantially identical thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions). In another embodiment, theanti-PD-1 antibody molecule comprises at least one, two, or three CDRsand/or hypervariable loops from a light chain variable region having anamino acid sequence of an antibody described herein, e.g., an antibodychosen from any of BAP049-hum01, BAP049-hum02, BAP049-hum03,BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08,BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13,BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E, assummarized in Table 1, or a sequence substantially identical thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions). In one embodiment, theanti-PD-1 antibody molecule comprises all six CDRs and/or hypervariableloops described herein, e.g., described in Table 1.

In one embodiment, the anti-PD-1 antibody molecule has a variable regionthat is identical in sequence, or which differs by 1, 2, 3, or 4 aminoacids from a variable region described herein (e.g., an FR regiondisclosed herein).

In one embodiment, the anti-PD-1 antibody molecule is a full antibody orfragment thereof (e.g., a Fab, F(ab′)₂, Fv, or a single chain Fvfragment (scFv)). In certain embodiments, the anti-PD-1 antibodymolecule is a monoclonal antibody or an antibody with singlespecificity. The anti-PD-1 antibody molecule can also be a humanized,chimeric, camelid, shark, or an in vitro-generated antibody molecule. Inone embodiment, the anti-PD-1 antibody molecule thereof is a humanizedantibody molecule. The heavy and light chains of the anti-PD-1 antibodymolecule can be full-length (e.g., an antibody can include at least one,and preferably two, complete heavy chains, and at least one, andpreferably two, complete light chains) or can include an antigen-bindingfragment (e.g., a Fab, F(ab′)₂, Fv, a single chain Fv fragment, a singledomain antibody, a diabody (dAb), a bivalent antibody, or bispecificantibody or fragment thereof, a single domain variant thereof, or acamelid antibody).

In certain embodiments, the anti-PD-1 antibody molecule is in the formof a bispecific or a multispecific antibody molecule. In one embodiment,the bispecific antibody molecule has a first binding specificity forPD-1 and a second binding specifity for TIM-3, LAG-3, CEACAM (e.g.,CEACAM-1, CEACAM-3, and/or CEACAM-5), PD-L1 or PD-L2. In one embodiment,the bispecific antibody molecule binds to PD-1 and TIM-3. In anotherembodiment, the bispecific antibody molecule binds to PD-1 and LAG-3. Inanother embodiment, the bispecific antibody molecule binds to PD-1 andCEACAM (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5). In anotherembodiment, the bispecific antibody molecule binds to PD-1 and CEACAM-1.In yet another embodiment, the bispecific antibody molecule binds toPD-1 and CEACAM-5. In another embodiment, the bispecific antibodymolecule binds to PD-1 and PD-L1. In yet another embodiment, thebispecific antibody molecule binds to PD-1 and PD-L2. Any combination ofthe aforesaid molecules can be made in a multispecific antibodymolecule, e.g., a trispecific antibody that includes a first bindingspecificity to PD-1, and a second and third binding specificity to oneor more of: TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3, orCEACAM-5), PD-L1 or PD-L2.

In other embodiments, the anti-PD-1 antibody molecule is used incombination with a bispecific molecule comprising one or more of: TIM-3,LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3, or CEACAM-5), PD-L1 or PD-L2.In one embodiment, the bispecific antibody molecule used in combinationbinds to CEACAM (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5) and LAG-3.In another embodiment, the bispecific antibody molecule used incombination binds to CEACAM (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5)and TIM-3. In another embodiment, the bispecific antibody molecule usedin combination binds to LAG-3 and TIM-3.

In yet other embodiments, the anti-PD-1 antibody molecule has a heavychain constant region (Fc) chosen from, e.g., the heavy chain constantregions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE;particularly, chosen from, e.g., the heavy chain constant regions ofIgG1, IgG2, IgG3, and IgG4, more particularly, the heavy chain constantregion of IgG1 or IgG2 (e.g., human IgG1, IgG2 or IgG4). In oneembodiment, the heavy chain constant region is human IgG1. In anotherembodiment, the anti-PD-1 antibody molecule has a light chain constantregion chosen from, e.g., the light chain constant regions of kappa orlambda, preferably kappa (e.g., human kappa). In one embodiment, theconstant region is altered, e.g., mutated, to modify the properties ofthe anti-PD-1 antibody molecule (e.g., to increase or decrease one ormore of: Fc receptor binding, antibody glycosylation, the number ofcysteine residues, effector cell function, or complement function). Forexample, the constant region is mutated at positions 296 (M to Y), 298(S to T), 300 (T to E), 477 (H to K) and 478 (N to F) to alter Fcreceptor binding (e.g., the mutated positions correspond to positions132 (M to Y), 134 (S to T), 136 (T to E), 313 (H to K) and 314 (N to F)of SEQ ID NOs: 212 or 214; or positions 135 (M to Y), 137 (S to T), 139(T to E), 316 (H to K) and 317 (N to F) of SEQ ID NOs: 215, 216, 217 or218). In another embodiment, the heavy chain constant region of an IgG4,e.g., a human IgG4, is mutated at position 228 according to EU numbering(e.g., S to P), e.g., as shown in Table 3. In certain embodiments, theanti-PD-1 antibody molecules comprises a human IgG4 mutated at position228 according to EU numbering (e.g., S to P), e.g., as shown in Table 3;and a kappa light chain constant region, e.g., as shown in Table 3. Instill another embodiment, the heavy chain constant region of an IgG1,e.g., a human IgG1, is mutated at one or more of position 297 accordingto EU numbering (e.g., N to A), position 265 according to EU numbering(e.g., D to A), position 329 according to EU numbering (e.g., P to A),position 234 according to EU numbering (e.g., L to A), or position 235according to EU numbering (e.g., L to A), e.g., as shown in Table 3. Incertain embodiments, the anti-PD-1 antibody molecules comprises a humanIgG1 mutated at one or more of the aforesaid positions, e.g., as shownin Table 3; and a kappa light chain constant region, e.g., as shown inTable 3.

In one embodiment, the anti-PD-1 antibody molecule is isolated orrecombinant.

In one embodiment, the anti-PD-1 antibody molecule is a humanizedantibody molecule. In one embodiment, the anti-PD-1 antibody moleculehas a risk score based on T cell epitope analysis of less than 700, 600,500, 400 or less.

In one embodiment, the anti-PD-1 antibody molecule is a humanizedantibody molecule and has a risk score based on T cell epitope analysisof 300 to 700, 400 to 650, 450 to 600, or a risk score as describedherein.

The invention also features a nucleic acid molecule that comprise one orboth nucleotide sequences that encode heavy and light chain variableregions, CDRs, hypervariable loops, framework regions of the anti-PD-1antibody molecules, as described herein. In certain embodiments, thenucleotide sequence that encodes the anti-PD-1 antibody molecule iscodon optimized. For example, the invention features a first and secondnucleic acid encoding heavy and light chain variable regions,respectively, of an anti-PD-1 antibody molecule chosen from one or moreof, e.g., any of BAP049-hum01, BAP049-hum02, BAP049-hum03, BAP049-hum04,BAP049-hum05, BAP049-hum06, BAP049-hum07, BAP049-hum08, BAP049-hum09,BAP049-hum10, BAP049-hum11, BAP049-hum12, BAP049-hum13, BAP049-hum14,BAP049-hum15, BAP049-hum16, BAP049-Clone-A, BAP049-Clone-B,BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E, as summarized inTable 1, or a sequence substantially identical thereto. For example, thenucleic acid can comprise a nucleotide sequence as set forth in Tables 1and 2, or a sequence substantially identical thereto (e.g., a sequenceat least about 85%, 90%, 95%, 99% or more identical thereto, or whichdiffers by no more than 3, 6, 15, 30, or 45 nucleotides from thesequences shown in Tables 1 and 2).

In other embodiments, the nucleic acid molecule comprises a nucleotidesequence that encodes a heavy chain variable domain and/or a heavy chainconstant region comprising the amino acid sequence of BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1; or the nucleotide sequence in Table 1; or asequence substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences.

In other embodiments, the nucleic acid molecule comprises a nucleotidesequence that encodes a light chain variable domain and/or a light chainconstant region comprising the amino acid sequence of BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E; or asdescribed in Table 1; or the nucleotide sequence in Table 1; or asequence substantially identical (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical) to any of the aforesaid sequences.

The aforesaid nucleotide sequences encoding the anti-PD-1 heavy andlight chain variable domain and constant regions can be present in aseparate nucleic acid molecule, or in the same nucleic acid molecule. Incertain embodiments, the nucleic acid molecules comprise a nucleotidesequence encoding a leader sequence, e.g., a leader sequence as shown inTable 4, or a sequence substantially identical thereto.

In certain embodiments, the nucleic acid molecule comprises a nucleotidesequence encoding at least one, two, or three CDRs, or hypervariableloops, from a heavy chain variable region having an amino acid sequenceas set forth in Table 1, or a sequence substantially homologous thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions).

In another embodiment, the nucleic acid molecule comprises a nucleotidesequence encoding at least one, two, or three CDRs, or hypervariableloops, from a light chain variable region having an amino acid sequenceas set forth in Table 1, or a sequence substantially homologous thereto(e.g., a sequence at least about 85%, 90%, 95%, 99% or more identicalthereto, and/or having one, two, three or more substitutions, insertionsor deletions, e.g., conserved substitutions).

In yet another embodiment, the nucleic acid molecule comprises anucleotide sequence encoding at least one, two, three, four, five, orsix CDRs, or hypervariable loops, from heavy and light chain variableregions having an amino acid sequence as set forth in Table 1, or asequence substantially homologous thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, and/or having one,two, three or more substitutions, insertions or deletions, e.g.,conserved substitutions).

In one embodiment, the nucleic acid molecule includes a nucleotidesequence encoding an anti-PD-1 antibody molecule that includes asubstitution in the light chain CDR3 at position 102 of the lightvariable region, e.g., a substitution of a cysteine to tyrosine, or acysteine to serine residue, at position 102 of the light variable regionaccording to Table 1 (e.g., SEQ ID NO: 16 or 24 for murine or chimeric,unmodified; or any of SEQ ID NOs: 34, 42, 46, 54, 58, 62, 66, 70, 74, or78 for a modified sequence).

In another embodiment, the nucleic acid molecule includes one or moreheavy chain framework region (e.g., any of VHFW1 (type a), VHFW1 (typeb), VHFW2 (type a), VHFW2 (type b), VHFW2 (type c), VHFW3 (type a),VHFW3 (type b), or VHFW4, or any combination thereof, e.g., a frameworkcombination as described herein) for any of BAP049-hum01, BAP049-hum02,BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06, BAP049-hum07,BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11, BAP049-hum12,BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16, BAP049-Clone-A,BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, or BAP049-Clone-E, assummarized in Table 1 and 2, or a sequence substantially identicalthereto. For example, the nucleic acid molecule can comprise anucleotide sequence as set forth in Tables 1 and 2, or a sequencesubstantially identical thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, or which differs by no morethan 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Tables1 and 2).

In another embodiment, the nucleic acid molecule includes one or morelight chain framework region (e.g., any of VLFW1 (type a), VLFW1 (typeb), VLFW1 (type c), VLFW1 (type d), VLFW1 (type e), VLFW2 (type a),VLFW2 (type b), VLFW2 (type c), VLFW3 (type a), VLFW3 (type b), VLFW3(type c), VLFW3 (type d), or VLFW4, or any combination thereof, e.g., aframework combination as described herein) for any of BAP049-hum01,BAP049-hum02, BAP049-hum03, BAP049-hum04, BAP049-hum05, BAP049-hum06,BAP049-hum07, BAP049-hum08, BAP049-hum09, BAP049-hum10, BAP049-hum11,BAP049-hum12, BAP049-hum13, BAP049-hum14, BAP049-hum15, BAP049-hum16,BAP049-Clone-A, BAP049-Clone-B, BAP049-Clone-C, BAP049-Clone-D, orBAP049-Clone-E, as summarized in Table 1 and 2, or a sequencesubstantially identical thereto. For example, the nucleic acid moleculecan comprise a nucleotide sequence as set forth in Tables 1 and 2, or asequence substantially identical thereto (e.g., a sequence at leastabout 85%, 90%, 95%, 99% or more identical thereto, or which differs byno more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown inTables 1 and 2).

In another embodiment, the nucleic acid molecule includes one or moreheavy chain framework region and one or more light chain frameworkregion as described herein. The heavy and light chain framework regionsmay be present in the same vector or separate vectors.

In another aspect, the application features host cells and vectorscontaining the nucleic acids described herein. The nucleic acids may bepresent in a single vector or separate vectors present in the same hostcell or separate host cell. The host cell can be a eukaryotic cell,e.g., a mammalian cell, an insect cell, a yeast cell, or a prokaryoticcell, e.g., E. coli. For example, the mammalian cell can be a culturedcell or a cell line. Exemplary mammalian cells include lymphocytic celllines (e.g., NSO), Chinese hamster ovary cells (CHO), COS cells, oocytecells, and cells from a transgenic animal, e.g., mammary epithelialcell.

In one aspect, the invention features a method of providing an antibodymolecule described herein. The method includes: providing a PD-1 antigen(e.g., an antigen comprising at least a portion of a PD-1 epitope);obtaining an antibody molecule that specifically binds to the PD-1polypeptide; and evaluating if the antibody molecule specifically bindsto the PD-1 polypeptide, or evaluating efficacy of the antibody moleculein modulating, e.g., inhibiting, the activity of the PD-1. The methodcan further include administering the antibody molecule to a subject,e.g., a human or non-human animal.

In another aspect, the invention provides, compositions, e.g.,pharmaceutical compositions, which include a pharmaceutically acceptablecarrier, excipient or stabilizer, and at least one of the anti-PD-1antibody molecules described herein. In one embodiment, the composition,e.g., the pharmaceutical composition, includes a combination of theantibody molecule and one or more agents, e.g., a therapeutic agent orother antibody molecule, as described herein. In one embodiment, theantibody molecule is conjugated to a label or a therapeutic agent.

The anti-PD-1 antibody molecules disclosed herein can inhibit, reduce orneutralize one or more activities of PD-1, resulting in blockade orreduction of an immune checkpoint. In one embodiment, the antibodymolecule results in one or more of: an increase in tumor infiltratinglymphocytes, an increase in T-cell receptor mediated proliferation, adecrease in immune evasion by cancerous cells, restoration of effectorcell function (e.g., one or more of T cell proliferation, IFN-γsecretion or cytolytic function), inhibition of regulatory T cellfunction, or an effect on the activity of multiple cell types, such asregulatory T cell, effector T cells and NK cells). Thus, such antibodymolecules can be used to treat or prevent disorders where enhancing animmune response in a subject is desired.

Uses of the Anti-PD-1 Antibody Molecules

Accordingly, in another aspect, a method of modulating an immuneresponse in a subject is provided. The method comprises administering tothe subject an anti-PD-1 antibody molecule disclosed herein (e.g., atherapeutically effective amount of an anti-PD-1 antibody molecule),alone or in combination with one or more agents or procedures, such thatthe immune response in the subject is modulated. In one embodiment, theantibody molecule enhances, stimulates or increases the immune responsein the subject. The subject can be a mammal, e.g., a primate, preferablya higher primate, e.g., a human (e.g., a patient having, or at risk ofhaving, a disorder described herein). In one embodiment, the subject isin need of enhancing an immune response. In one embodiment, the subjecthas, or is at risk of, having a disorder described herein, e.g., acancer or an infectious disorder as described herein. In certainembodiments, the subject is, or is at risk of being, immunocompromised.For example, the subject is undergoing or has undergone achemotherapeutic treatment and/or radiation therapy. Alternatively, orin combination, the subject is, or is at risk of being,immunocompromised as a result of an infection.

In one aspect, a method of treating (e.g., one or more of reducing,inhibiting, or delaying progression) a cancer or a tumor in a subject isprovided. The method comprises administering to the subject an anti-PD-1antibody molecule described herein, e.g., a therapeutically effectiveamount of an anti-PD-1 antibody molecule, alone or in combination withone or more agents or procedures. In certain embodiments, the anti-PD-1antibody molecule is administered in combination with a modulator of acostimulatory molecule (e.g., an agonist of a costimulatory molecule) ora modulator of an inhibitory molecule (e.g., an inhibitor of an immunecheckpoint inhibitor), e.g., as described herein.

In certain embodiments, the cancer treated with the anti-PD-1 antibodymolecule, includes but is not limited to, a solid tumor, a hematologicalcancer (e.g., leukemia, lymphoma, myeloma, e.g., multiple myeloma), anda metastatic lesion. In one embodiment, the cancer is a solid tumor.Examples of solid tumors include malignancies, e.g., sarcomas andcarcinomas, e.g., adenocarcinomas of the various organ systems, such asthose affecting the lung, breast, ovarian, lymphoid, gastrointestinal(e.g., colon), anal, genitals and genitourinary tract (e.g., renal,urothelial, bladder cells, prostate), pharynx, CNS (e.g., brain, neuralor glial cells), head and neck, skin (e.g., melanoma), and pancreas, aswell as adenocarcinomas which include malignancies such as coloncancers, rectal cancer, renal-cell carcinoma, liver cancer, non-smallcell lung cancer, cancer of the small intestine and cancer of theesophagus. The cancer may be at an early, intermediate, late stage ormetastatic cancer.

In one embodiment, the cancer is chosen from a lung cancer (e.g., anon-small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/ornon-squamous histology, or a NSCLC adenocarcinoma)), a melanoma (e.g.,an advanced melanoma), a renal cancer (e.g., a renal cell carcinoma), aliver cancer, a myeloma (e.g., a multiple myeloma), a prostate cancer, abreast cancer (e.g., a breast cancer that does not express one, two orall of estrogen receptor, progesterone receptor, or Her2/neu, e.g., atriple negative breast cancer), a colorectal cancer, a pancreaticcancer, a head and neck cancer (e.g., head and neck squamous cellcarcinoma (HNSCC), anal cancer, gastro-esophageal cancer, thyroidcancer, cervical cancer, a lymphoproliferative disease (e.g., apost-transplant lymphoproliferative disease) or a hematological cancer,T-cell lymphoma, B-cell lymphoma, a non-Hogdkin lymphoma, or a leukemia(e.g., a myeloid leukemia or a lymphoid leukemia).

In another embodiment, the cancer is chosen form a carcinoma (e.g.,advanced or metastatic carcinoma), melanoma or a lung carcinoma, e.g., anon-small cell lung carcinoma.

In one embodiment, the cancer is a lung cancer, e.g., a non-small celllung cancer or small cell lung cancer.

In one embodiment, the cancer is a melanoma, e.g., an advanced melanoma.In one embodiment, the cancer is an advanced or unresectable melanomathat does not respond to other therapies. In other embodiments, thecancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation).In yet other embodiments, the anti-PD-1 antibody molecule isadministered after treatment with an anti-CTLA4 antibody (e.g.,ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib ordabrafenib).

In another embodiment, the cancer is a hepatocarcinoma, e.g., anadvanced hepatocarcinoma, with or without a viral infection, e.g., achronic viral hepatitis.

In another embodiment, the cancer is a prostate cancer, e.g., anadvanced prostate cancer. In yet another embodiment, the cancer is amyeloma, e.g., multiple myeloma.

In yet another embodiment, the cancer is a renal cancer, e.g., a renalcell carcinoma (RCC) (e.g., a metastatic RCC or clear cell renal cellcarcinoma (CCRCC)).

In one embodiment, the cancer microenvironment has an elevated level ofPD-L1 expression. Alternatively, or in combination, the cancermicroenvironment can have increased IFNγ and/or CD8 expression.

In some embodiments, the subject has, or is identified as having, atumor that has one or more of high PD-L1 level or expression, or asbeing Tumor Infiltrating Lymphocyte (TIL)+(e.g., as having an increasednumber of TILs), or both. In certain embodiments, the subject has, or isidentified as having, a tumor that has high PD-L1 level or expressionand that is TIL+. In some embodiments, the methods described hereinfurther include identifying a subject based on having a tumor that hasone or more of high PD-L1 level or expression, or as being TIL+, orboth. In certain embodiments, the methods described herein furtherinclude identifying a subject based on having a tumor that has highPD-L1 level or expression and as being TIL+. In some embodiments, tumorsthat are TIL+ are positive for CD8 and IFNγ. In some embodiments, thesubject has, or is identified as having, a high percentage of cells thatare positive for one, two or more of PD-L1, CD8, and/or IFNγ. In certainembodiments, the subject has or is identified as having a highpercentage of cells that are positive for all of PD-L1, CD8, and IFNγ.

In some embodiments, the methods described herein further includeidentifying a subject based on having a high percentage of cells thatare positive for one, two or more of PD-L1, CD8, and/or IFNγ. In certainembodiments, the methods described herein further include identifying asubject based on having a high percentage of cells that are positive forall of PD-L1, CD8, and IFNγ. In some embodiments, the subject has, or isidentified as having, one, two or more of PD-L1, CD8, and/or IFNγ, andone or more of a lung cancer, e.g., squamous cell lung cancer or lungadenocarcinoma; a head and neck cancer; a squamous cell cervical cancer;a stomach cancer; an esophageal cancer; a thyroid cancer; a melanoma,and/or a nasopharyngeal cancer (NPC). In certain embodiments, themethods described herein further describe identifying a subject based onhaving one, two or more of PD-L1, CD8, and/or IFNγ, and one or more of alung cancer, e.g., squamous cell lung cancer or lung adenocarcinoma; ahead and neck cancer; a squamous cell cervical cancer; a stomach cancer;a thyroid cancer; a melanoma, and or a nasopharyngeal cancer.

Methods and compositions disclosed herein are useful for treatingmetastatic lesions associated with the aforementioned cancers.

In a further aspect, the invention provides a method of treating aninfectious disease in a subject, comprising administering to a subject atherapeutically effective amount of an anti-PD-1 antibody moleculedescribed herein, alone or in combination with one or more agents orprocedures. In one embodiment, the infection disease is chosen fromhepatitis (e.g., hepatis C infection), or sepsis.

Still further, the invention provides a method of enhancing an immuneresponse to an antigen in a subject, comprising administering to thesubject: (i) the antigen; and (ii) an anti-PD-1 antibody molecule, suchthat an immune response to the antigen in the subject is enhanced. Theantigen can be, for example, a tumor antigen, a viral antigen, abacterial antigen or an antigen from a pathogen.

The anti-PD-1 antibody molecule can be administered to the subjectsystemically (e.g., orally, parenterally, subcutaneously, intravenously,rectally, intramuscularly, intraperitoneally, intranasally,transdermally, or by inhalation or intracavitary installation),topically, or by application to mucous membranes, such as the nose,throat and bronchial tubes.

Dosages and therapeutic regimens of the anti-PD-1 antibody molecule canbe determined by a skilled artisan. In certain embodiments, theanti-PD-1 antibody molecule is administered by injection (e.g.,subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g.,about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about3 mg/kg. The dosing schedule can vary from e.g., once a week to onceevery 2, 3, or 4 weeks. In one embodiment, the anti-PD-1 antibodymolecule is administered at a dose from about 10 to 20 mg/kg every otherweek.

The antibody molecules described herein are preferred for use in themethods described herein, although other anti-PD-1 antibodies can beused instead, or in combination with an anti-PD-1 antibody molecule ofthe invention.

Combination Therapies

The methods and compositions described herein can be used in combinationwith other agents or therapeutic modalities. In one embodiment, themethods described herein include administering to the subject ananti-PD-1 antibody molecule as described herein, in combination with anagent or therapeutic procedure or modality, in an amount effective totreat or prevent a disorder. The anti-PD-1 antibody molecule and theagent or therapeutic procedure or modality can be administeredsimultaneously or sequentially in any order. Any combination andsequence of the anti-PD-1 antibody molecules and other therapeuticagents, procedures or modalities (e.g., as described herein) can beused. The antibody molecule and/or other therapeutic agents, proceduresor modalities can be administered during periods of active disorder, orduring a period of remission or less active disease. The antibodymolecule can be administered before the other treatment, concurrentlywith the treatment, post-treatment, or during remission of the disorder.

In certain embodiments, the methods and compositions described hereinare administered in combination with one or more of other antibodymolecules, chemotherapy, other anti-cancer therapy (e.g., targetedanti-cancer therapies, gene therapy, viral therapy, RNA therapy bonemarrow transplantation, nanotherapy, or oncolytic drugs), cytotoxicagents, immune-based therapies (e.g., cytokines or cell-based immunetherapies), surgical procedures (e.g., lumpectomy or mastectomy) orradiation procedures, or a combination of any of the foregoing. Theadditional therapy may be in the form of adjuvant or neoadjuvanttherapy. In some embodiments, the additional therapy is an enzymaticinhibitor (e.g., a small molecule enzymatic inhibitor) or a metastaticinhibitor. Exemplary cytotoxic agents that can be administered incombination with include antimicrotubule agents, topoisomeraseinhibitors, anti-metabolites, mitotic inhibitors, alkylating agents,anthracyclines, vinca alkaloids, intercalating agents, agents capable ofinterfering with a signal transduction pathway, agents that promoteapoptosis, proteosome inhibitors, and radiation (e.g., local or wholebody irradiation (e.g., gamma irradiation). In other embodiments, theadditional therapy is surgery or radiation, or a combination thereof. Inother embodiments, the additional therapy is a therapy targeting one ormore of PI3K/AKT/mTOR pathway, an HSP90 inhibitor, or a tubulininhibitor.

Alternatively, or in combination with the aforesaid combinations, themethods and compositions described herein can be administered incombination with one or more of: an immunomodulator (e.g., an activatorof a costimulatory molecule or an inhibitor of an inhibitory molecule,e.g., an immune checkpoint molecule); a vaccine, e.g., a therapeuticcancer vaccine; or other forms of cellular immunotherapy.

Exemplary non-limiting combinations and uses of the anti-PD-1 antibodymolecules include the following.

In certain embodiments, the anti-PD-1 antibody molecule is administeredin combination with a modulator of a costimulatory molecule or aninhibitory molecule, e.g., a co-inhibitory ligand or receptor.

In one embodiment, the anti-PD-1 antibody molecule is administered incombination with a modulator, e.g., agonist, of a costimulatorymolecule. In one embodiment, the agonist of the costimulatory moleculeis chosen from an agonist (e.g., an agonistic antibody orantigen-binding fragment thereof, or a soluble fusion) of OX40, CD2,CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137),GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160,B7-H3 or CD83 ligand.

In one embodiment, the anti-PD-1 antibody molecule is administered incombination with an inhibitor of an inhibitory (or immune checkpoint)molecule chosen from PD-L1, PD-L2, CTLA-4, TIM-3, LAG-3, CEACAM (e.g.,CEACAM-1, CEACAM-3, and/or CEACAM-5), VISTA, BTLA, TIGIT, LAIR1, CD160,2B4 and/or TGFR beta. Inhibition of an inhibitory molecule can beperformed by inhibition at the DNA, RNA or protein level. Inembodiments, an inhibitory nucleic acid (e.g., a dsRNA, siRNA or shRNA),can be used to inhibit expression of an inhibitory molecule. In otherembodiments, the inhibitor of an inhibitory signal is, a polypeptidee.g., a soluble ligand, or an antibody or antigen-binding fragmentthereof, that binds to the inhibitory molecule. In one embodiment, theinhibitor is a soluble ligand (e.g., a CTLA-4-Ig), or an antibody orantibody fragment that binds to PD-L1, PD-L2 or CTLA-4. For example, theanti-PD-1 antibody molecule can be administered in combination with ananti-CTLA-4 antibody, e.g., ipilimumab, for example, to treat a cancer(e.g., a cancer chosen from: a melanoma, e.g., a metastatic melanoma; alung cancer, e.g., a non-small cell lung carcinoma; or a prostatecancer). In one embodiment, the anti-PD-1 antibody molecule isadministered after treatment with an anti-CTLA-4 antibody (e.g.,ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib ordabrafenib).

In another embodiment, the anti-PD-1 antibody molecule is administeredin combination with an anti-LAG-3 antibody or antigen-binding fragmentthereof.

In another embodiment, the anti-PD-1 antibody molecule is administeredin combination with an anti-TIM-3 antibody or antigen-binding fragmentthereof.

In yet other embodiments, the anti-PD-1 antibody molecule isadministered in combination with an anti-LAG-3 antibody and ananti-TIM-3 antibody (or antigen-binding fragments thereof).

In another embodiment, the anti-PD-1 antibody molecule is administeredin combination with a CEACAM inhibitor (e.g., CEACAM-1 and/or CEACAM-5inhibitor), e.g., an anti-CEACAM antibody molecule. In anotherembodiment, the anti-PD-1 antibody molecule is administered incombination with a CEACAM-1 inhibitor, e.g., an anti-CEACAM-1 antibodymolecule. In another embodiment, the anti-PD-1 antibody molecule isadministered in combination with a CEACAM-5 inhibitor, e.g., ananti-CEACAM-5 antibody molecule. The combination of antibodies recitedherein can be administered separately, e.g., as separate antibodies orantigen-binding fragments thereof, or linked, e.g., as a bispecific ortrispecific antibody molecule. In one embodiment, a bispecific antibodythat includes an anti-PD-1 antibody molecule and an anti-TIM-3,anti-CEACAM (e.g., anti-CEACAM-1, CEACAM-3, and/or anti-CEACAM-5), oranti-LAG-3 antibody, or an antigen-binding fragment thereof, isadministered. In certain embodiments, the combination of antibodiesrecited herein is used to treat a cancer, e.g., a cancer as describedherein (e.g., a solid tumor or a hematologic malignancy).

In other embodiments, the anti-PD-1 antibody molecule is administered incombination with a cytokine. The cytokine can be administered as afusion molecule to the anti-PD-1 antibody molecule, or as separatecompositions. In one embodiment, the anti-PD-1 antibody is administeredin combination with one, two, three or more cytokines, e.g., as a fusionmolecule or as separate compositions. In one embodiment, the cytokine isan interleukin (IL) chosen from one, two, three or more of IL-1, IL-2,IL-12, IL-15 or IL-21. In one embodiment, a bispecific antibody moleculehas a first binding specificity to a first target (e.g., to PD-1), asecond binding specificity to a second target (e.g., LAG-3 or TIM-3),and is optionally linked to an interleukin (e.g., IL-12) domain e.g.,full length IL-12 or a portion thereof. In certain embodiments, thecombination of anti-PD-1 antibody molecule and the cytokine describedherein is used to treat a cancer, e.g., a cancer as described herein(e.g., a solid tumor).

In certain embodiments, the anti-PD-1 antibody molecule is administeredin combination with an antibody specific against an HLA C, e.g., anantibody specific to Killer-cell Immunoglobulin-like Receptors (alsoreferred to herein as an “anti-KIR antibody”). In certain embodiments,the combination of anti-PD-1 antibody molecule and anti-KIR antibody isused to treat a cancer, e.g., a cancer as described herein (e.g., asolid tumor, e.g., an advanced solid tumor).

In one embodiment, the anti-PD-1 antibody molecule is administered incombination with a cellular immunotherapy (e.g., Provenge® (e.g.,Sipuleucel-T)), and optionally in combination with cyclophosphamide. Incertain embodiments, the combination of anti-PD-1 antibody molecule,Provenge® and/or cyclophosphamide is used to treat a cancer, e.g., acancer as described herein (e.g., a prostate cancer, e.g., an advancedprostate cancer).

In another embodiment, the anti-PD-1 antibody molecule is administeredin combination with a vaccine, e.g., a cancer vaccine, (e.g., adendritic cell renal carcinoma (DC-RCC) vaccine). In one embodiment, thevaccine is peptide-based, DNA-based, RNA-based, or antigen-based, or acombination thereof. In embodiments, the vaccine comprises one or morepeptides, nucleic acids (e.g., DNA or RNA), antigens, or a combinationthereof. In certain embodiments, the combination of anti-PD-1 antibodymolecule and the DC-RCC vaccine is used to treat a cancer, e.g., acancer as described herein (e.g., a renal carcinoma, e.g., metastaticrenal cell carcinoma (RCC) or clear cell renal cell carcinoma (CCRCC)).

In another embodiment, the anti-PD-1 antibody molecule is administeredin combination with an adjuvant.

In yet another embodiment, the anti-PD-1 antibody molecule isadministered in combination with chemotherapy, and/or immunotherapy. Forexample, the anti-PD-1 antibody molecule can be used to treat a myeloma,alone or in combination with one or more of: chemotherapy or otheranti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), ananti-TIM-3 antibody, tumor antigen-pulsed dendritic cells, fusions(e.g., electrofusions) of tumor cells and dendritic cells, orvaccination with immunoglobulin idiotype produced by malignant plasmacells. In one embodiment, the anti-PD-1 antibody molecule is used incombination with an anti-TIM-3 antibody to treat a myeloma, e.g., amultiple myeloma.

In one embodiment, the anti-PD-1 antibody molecule is used incombination with chemotherapy to treat a lung cancer, e.g., non-smallcell lung cancer. In one embodiment, the anti-PD-1 antibody molecule isused with standard lung, e.g., NSCLC, chemotherapy, e.g., platinumdoublet therapy, to treat lung cancer. In yet other embodiments, theanti-PD-1 antibody molecule is used in combination with anindolearnine-pyrrole 2,3-dioxygenase (IDO) inhibitor (e.g.,(4E)-4-[(3-chloro-4-fluoroanilino)-nitrosomethylidene]-1,2,5-oxadiazol-3-amine(also known as INCB24360), indoximod (1-methyl-D-tryptophan),α-cyclohexyl-5H-Imidazo[5,1-a]isoindole-5-ethanol (also known asNLG919), etc.) in a subject with advanced or metastatic cancer (e.g., apatient with metastic and recurrent NSCL cancer).

In yet other embodiments, the anti-PD-1 antibody molecule is used incombination with one or more of: an immune-based strategy (e.g.,interleukin-2 or interferon-α), a targeting agent (e.g., a VEGFinhibitor such as a monoclonal antibody to VEGF); a VEGF tyrosine kinaseinhibitor such as sunitinib, sorafenib, axitinib and pazopanib; an RNAiinhibitor; or an inhibitor of a downstream mediator of VEGF signaling,e.g., an inhibitor of the mammalian target of rapamycin (mTOR), e.g.,everolimus and temsirolimus. Any of such combinations can be used totreat a renal cancer, e.g., renal cell carcinoma (RCC) (e.g., clear cellrenal cell carcinoma (CCRCC)) or metastatic RCC.

In some embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used in combinationwith a MEK inhibitor (e.g., a MEK inhibitor as described herein). Insome embodiments, the combination of the anti-PD-1 antibody and the MEKinhibitor is used to treat a cancer (e.g., a cancer described herein).In some embodiments, the cancer treated with the combination is chosenfrom a melanoma, a colorectal cancer, a non-small cell lung cancer, anovarian cancer, a breast cancer, a prostate cancer, a pancreatic cancer,a hematological malignancy or a renal cell carcinoma. In certainembodiments, the cancer includes a BRAF mutation (e.g., a BRAF V600Emutation), a BRAF wildtype, a KRAS wildtype or an activating KRASmutation. The cancer may be at an early, intermediate or late stage.

In another embodiment, the anti-PD-1 antibody molecule is used incombination with one, two or all of oxaliplatin, leucovorin or 5-FU(e.g., a FOLFOX co-treatment). Alternatively or in combination,combination further includes a VEGF inhibitor (e.g., a VEGF inhibitor asdisclosed herein). In some embodiments, the combination of the anti-PD-1antibody, the FOLFOX co-treatment, and the VEGF inhibitor is used totreat a cancer (e.g., a cancer described herein). In some embodiments,the cancer treated with the combination is chosen from a melanoma, acolorectal cancer, a non-small cell lung cancer, an ovarian cancer, abreast cancer, a prostate cancer, a pancreatic cancer, a hematologicalmalignancy or a renal cell carcinoma. The cancer may be at an early,intermediate or late stage.

In other embodiments, the anti-PD-1 antibody molecule is administeredwith a tyrosine kinase inhibitor (e.g., axitinib) to treat renal cellcarcinoma and other solid tumors.

In other embodiments, the anti-PD-1 antibody molecule is administeredwith a 4-1BB receptor targeting agent (e.g., an antibody that stimulatessignaling through 4-1BB (CD-137), e.g., PF-2566). In one embodiment, theanti-PD-1 antibody molecule is administered in combination with atyrosine kinase inhibitor (e.g., axitinib) and a 4-1BB receptortargeting agent.

The anti-PD-1 antibody molecule can be bound to a substance, e.g., acytotoxic agent or moiety (e.g., a therapeutic drug; a compound emittingradiation; molecules of plant, fungal, or bacterial origin; or abiological protein (e.g., a protein toxin) or particle (e.g., arecombinant viral particle, e.g., via a viral coat protein). Forexample, the antibody can be coupled to a radioactive isotope such as anα-, β-, or γ-emitter, or a β- and γ-emitter.

Any combination and sequence of the anti-PD-1 antibody molecules andother therapeutic agents, procedures or modalities (e.g., as describedherein) can be used. The antibody molecule and/or other therapeuticagents, procedures or modalities can be administered during periods ofactive disorder, or during a period of remission or less active disease.The antibody molecule can be administered before the other treatment,concurrently with the treatment, post-treatment, or during remission ofthe disorder.

Additional Combination Therapies

The methods and compositions described herein (e.g., PD-1 antibodies andmethods of using them) can be used in combination with other agents ortherapeutic modalities, e.g., a second therapeutic agent chosen from oneor more of the agents listed in Table 7. In one embodiment, the methodsdescribed herein include administering to the subject an anti-PD-1antibody molecule as described herein (optionally in combination withone or more inhibitors of PD-L1, LAG-3, TIM-3, CEACAM (e.g., CEACAM-1and/or CEACAM-5), or CTLA-4)), further include administration of asecond therapeutic agent chosen from one or more of the agents listed inTable 7, in an amount effective to treat or prevent a disorder, e.g., adisorder as described herein, e.g., a cancer. When administered incombination, the anti-PD-1 antibody molecule, the additional agent(e.g., second or third agent), or all, can be administered in an amountor dose that is higher, lower or the same than the amount or dosage ofeach agent used individually, e.g., as a monotherapy. In certainembodiments, the administered amount or dosage of the anti-PD-1antibody, the additional agent (e.g., second or third agent), or all, islower (e.g., at least 20%, at least 30%, at least 40%, or at least 50%)than the amount or dosage of each agent used individually, e.g., as amonotherapy. In other embodiments, the amount or dosage of the anti-PD-1antibody, the additional agent (e.g., second or third agent), or all,that results in a desired effect (e.g., treatment of cancer) is lower(e.g., at least 20%, at least 30%, at least 40%, or at least 50% lower).

In other embodiments, the second therapeutic agent is chosen from one ormore of the agents listed in Table 7. In one embodiment, the cancer ischosen from a lung cancer (e.g., a non-small cell lung cancer (NSCLC)(e.g., a NSCLC with squamous and/or non-squamous histology, or a NSCLCadenocarcinoma), or disclosed in a publication listed in Table 7. Insome embodiments, the second therapeutic agent is chosen from one ormore of: 1) a protein kinase C (PKC) inhibitor; 2) a heat shock protein90 (HSP90) inhibitor; 3) an inhibitor of a phosphoinositide 3-kinase(PI3K) and/or target of rapamycin (mTOR); 4) an inhibitor of cytochromeP450 (e.g., a CYP17 inhibitor or a 17alpha-Hydroxylase/C17-20 Lyaseinhibitor); 5) an iron chelating agent; 6) an aromatase inhibitor; 7) aninhibitor of p53, e.g., an inhibitor of a p53/Mdm2 interaction; 8) anapoptosis inducer; 9) an angiogenesis inhibitor; 10) an aldosteronesynthase inhibitor; 11) a smoothened (SMO) receptor inhibitor; 12) aprolactin receptor (PRLR) inhibitor; 13) a Wnt signaling inhibitor; 14)a CDK4/6 inhibitor; 15) a fibroblast growth factor receptor 2(FGFR2)/fibroblast growth factor receptor 4 (FGFR4) inhibitor; 16) aninhibitor of macrophage colony-stimulating factor (M-CSF); 17) aninhibitor of one or more of c-KIT, histamine release, Flt3 (e.g.,FLK2/STK1) or PKC; 18) an inhibitor of one or more of VEGFR-2 (e.g.,FLK-1/KDR), PDGFRbeta, c-KIT or Raf kinase C; 19) a somatostatin agonistand/or a growth hormone release inhibitor; 20) an anaplastic lymphomakinase (ALK) inhibitor; 21) an insulin-like growth factor 1 receptor(IGF-1R) inhibitor; 22) a P-Glycoprotein 1 inhibitor; 23) a vascularendothelial growth factor receptor (VEGFR) inhibitor; 24) a BCR-ABLkinase inhibitor; 25) an FGFR inhibitor; 26) an inhibitor of CYP11B2;27) a HDM2 inhibitor, e.g., an inhibitor of the HDM2-p53 interaction;28) an inhibitor of a tyrosine kinase; 29) an inhibitor of c-MET; 30) aninhibitor of JAK; 31) an inhibitor of DAC; 32) an inhibitor of11β-hydroxylase; 33) an inhibitor of IAP; 34) an inhibitor of PIMkinase; 35) an inhibitor of Porcupine; 36) an inhibitor of BRAF, e.g.,BRAF V600E or wild-type BRAF; 37) an inhibitor of HER3; 38) an inhibitorof MEK; or 39) an inhibitor of a lipid kinase, e.g., as described hereinand in Table 7.

In one embodiment, the second therapeutic agent is chosen from one ormore of: Compound A8, Compound A17, Compound A23, Compound A24, CompoundA27, Compound A29, Compound A33, and Compound A13.

In other embodiments, the second therapeutic agent is chosen from one ormore of: Compound A5, Compound A8, Compound A17, Compound A23, CompoundA24, Compound A29, and Compound A40.

In other embodiments, the second therapeutic agent is chosen from one ormore of: Compound A9, Compound A16, Compound A17, Compound A21, CompoundA22, Compound A25, Compound A28, Compound A48, and Compound 49.

In embodiments, the second therapeutic agent is administered at atherapeutic or lower-than therapeutic dose. In certain embodiments, theconcentration of the second therapeutic agent that is required toachieve inhibition, e.g., growth inhibition, is lower when the secondtherapeutic agent is administered in combination with the anti-PD-1antibody molecule than when the second therapeutic agent is administeredindividually. In certain embodiments, the concentration of the anti-PD-1antibody molecule that is required to achieve inhibition, e.g., growthinhibition, is lower when the anti-PD-1 antibody molecule isadministered in combination with the second therapeutic agent than whenthe anti-PD-1 antibody molecule is administered individually. In certainembodiments, in a combination therapy, the concentration of the secondtherapeutic agent that is required to achieve inhibition, e.g., growthinhibition, is lower than the therapeutic dose of the second therapeuticagent as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%,60-70%, 70-80%, or 80-90% lower. In certain embodiments, in acombination therapy, the concentration of the anti-PD-1 antibodymolecule that is required to achieve inhibition, e.g., growthinhibition, is lower than the therapeutic dose of the anti-PD-1 antibodymolecule as a monotherapy, e.g., 10-20%, 20-30%, 30-40%, 40-50%, 50-60%,60-70%, 70-80%, or 80-90% lower.

Detection

In another aspect, the invention features methods for detecting thepresence of PD-1 in a sample, e.g., in vitro or in vivo (e.g., abiological sample, e.g., serum, semen or urine, or a tissue biopsy,e.g., from a hyperproliferative or cancerous lesion). The subject methodcan be used to evaluate (e.g., monitor treatment or progression of,diagnose and/or stage a disorder described herein, e.g., ahyperproliferative or cancerous disorder, in a subject). The methodincludes: (i) contacting the sample with (and optionally, a reference,e.g., a control sample), or administering to the subject, an antibodymolecule as described herein, under conditions that allow interaction tooccur, and (ii) detecting formation of a complex between the antibodymolecule, and the sample (and optionally, the reference, e.g., control,sample). Formation of the complex is indicative of the presence of PD-1,and can indicate the suitability or need for a treatment describedherein. The method can involve an immunohistochemistry,immunocytochemistry, FACS, antibody molecule complexed magnetic beads,ELISA assays, PCR-techniques (e.g., RT-PCR).

Typically, the antibody molecule used in the in vivo and in vitrodiagnostic methods is directly or indirectly labeled with a detectablesubstance to facilitate detection of the bound or unbound binding agent.Suitable detectable substances include various biologically activeenzymes, prosthetic groups, fluorescent materials, luminescentmaterials, paramagnetic (e.g., nuclear magnetic resonance active)materials, and radioactive materials.

Additional embodiments provide a method of treating a cancer,comprising: identifying in a subject or a sample (e.g., a subject'ssample comprising cancer cells and optionally immune cells such as TILs)the presence of one, two or all of PD-L1, CD8, or IFN-γ, therebyproviding a value for one, two or all of PD-L1, CD8, and IFN-γ. Themethod can further include comparing the PD-L1, CD8, and/or IFN-γ valuesto a reference value, e.g., a control value. If the PD-L1, CD8, and/orIFN-γ values are greater than the reference value, e.g., the controlvalues, administering a therapeutically effective amount of an anti-PD-1antibody (e.g., an anti-PD-1 antibody described herein) to the subject,optionally in combination with one or more other agents, therebytreating the cancer. The cancer may be, e.g., a cancer described herein,such as lung cancer (squamous), lung cancer (adenocarcinoma), head andneck cancer, cervical cancer (squamous), stomach cancer, thyroid cancer,melanoma, nasopharyngeal cancer, or breast cancer, e.g., TN breastcancer, e.g., IM-TN breast cancer. In some embodiments, the cancer isER+ breast cancer or pancreatic cancer.

Also provided is a method of treating a cancer, comprising: testing asubject or a sample (e.g., a subject's sample comprising cancer cells)for the presence of PD-L1, thereby identifying a PD-L1 value, comparingthe PD-L1 value to a control value, and if the PD-L1 value is greaterthan the control value, administering a therapeutically effective amountof an anti-PD-1 antibody (e.g., an anti-PD-1 antibody described herein)to the subject, optionally in combination with one or more other agents,thereby treating the cancer. The cancer may be, e.g., a cancer asdescribed herein, such as cancer is non-small cell lung (NSCLC)adenocarcinoma (ACA), NSCLC squamous cell carcinoma (SCC), orhepatocellular carcinoma (HCC).

In another aspect, the invention features diagnostic or therapeutic kitsthat include the antibody molecules described herein and instructionsfor use.

All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety.

Other features, objects, and advantages of the invention will beapparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the amino acid sequences of the light and heavy chainvariable regions of murine anti-PD-1 mAb BAP049. The upper and lowersequences were from two independent analyses. The light and heavy chainCDR sequences based on Kabat numbering are underlined. The light heavychain CDR sequences based on Chothia numbering are shown in bolditalics. The unpaired Cys residue at position 102 of the light chainsequence is boxed. Sequences are disclosed as SEQ ID NOs: 8, 228, 16 and229, respectively, in order of appearance.

FIG. 2A depicts the amino acid sequences of the light and heavy chainvariable regions of murine anti-PD-1 mAb BAP049 aligned with thegermline sequences. The upper and lower sequences are the germline (GL)and BAP049 (Mu mAb) sequences, respectively. The light and heavy chainCDR sequences based on Kabat numbering are underlined. The light heavychain CDR sequences based on Chothia numbering are shown in bolditalics. “−” means identical amino acid residue. Sequences disclosed asSEQ ID NOs: 230, 8, 231 and 16, respectively, in order of appearance.

FIG. 2B depicts the sequence of murine κ J2 gene and the correspondingmutation in murine anti-PD-1 mAb BAP049. “−” means identical nucleotideresidue. Sequences disclosed as SEQ ID NOs: 233, 232, 234 and 235,respectively, in order of appearance.

FIGS. 3A-3B depict the competition binding between fluorescently labeledmurine anti-PD-1 mAb BAP049 (Mu mAb) and three chimeric versions ofBAP049 (Chi mAb). Experiment was performed twice, and the results areshown in FIGS. 3A and 3B, respectively. The three chimeric BAP049antibodies (Chi mAb (Cys), Chi mAb (Tyr) and Chi mAb (Ser)) have Cys,Tyr and Ser residue at position 102 of the light chain variable region,respectively. Chi mAb (Cys), Chi mAb (Tyr) and Chi mAb (Ser) are alsoknown as BAP049-chi, BAP049-chi-Y, and BAP049-chi-S, respectively.

FIG. 4 is a bar graph showing the results of FACS binding analysis forthe sixteen humanized BAP049 clones (BAP049-hum01 to BAP049-hum16). Theantibody concentrations are 200, 100, 50, 25 and 12.5 ng/ml from theleftmost bar to the rightmost bar for each tested mAb.

FIG. 5 depicts the structural analysis of the humanized BAP049 clones(a, b, c, d and e represent various types of framework regionsequences). The concentrations of the mAbs in the samples are alsoshown.

FIG. 6A-6B depicts the binding affinity and specificity of humanizedBAP049 mAbs measured in a competition binding assay using a constantconcentration of Alexa 488-labeled murine mAb BAP049, serial dilutionsof the test antibodies, and PD-1-expressing 300.19 cells.

Experiment was performed twice, and the results are shown in FIGS. 6Aand 6B, respectively.

FIG. 7 depicts the ranking of humanized BAP049 clones based on FACSdata, competition binding and structural analysis. The concentrations ofthe mAbs in the samples are also shown.

FIGS. 8A-8B depict blocking of ligand binding to PD-1 by selectedhumanized BAP049 clones. Blocking of PD-L1-Ig and PD-L2-Ig binding toPD-1 is shown in FIG. 8A. Blocking of PD-L2-Ig binding to PD-1 is shownin FIG. 8B. BAP049-hum01, BAP049-hum05, BAP049-hum08, BAP049-hum09,BAP049-hum10, and BAP049-hum11 were evaluated. Murine mAb BAP049 andchimeric mAb having Tyr at position 102 of the light chain variableregion were also included in the analyses.

FIGS. 9A-9B depict the alignment of heavy chain variable domainsequences for the sixteen humanized BAP049 clones and BAP049 chimera(BAP049-chi). In FIG. 9A, all of the sequences are shown (SEQ ID NOs:22, 38, 38, 38, 38, 38, 38, 38, 38, 38, 50, 50, 50, 50, 82, 82 and 86,respectively, in order of appearance). In FIG. 9B, only amino acidsequences that are different from mouse sequence are shown (SEQ ID NOs:22, 38, 38, 38, 38, 38, 38, 38, 38, 38, 50, 50, 50, 50, 82, 82 and 86,respectively, in order of appearance).

FIGS. 10A-10B depict the alignment of light chain variable domainsequences for the sixteen humanized BAP049 clones and BAP049 chimera(BAP049-chi). In FIG. 10A, all of the sequences are shown (SEQ ID NOs:24, 66, 66, 66, 66, 70, 70, 70, 58, 62, 78, 74, 46, 46, 42, 54 and 54,respectively, in order of appearance). In FIG. 10B, only amino acidsequences that are different from mouse sequence are shown (SEQ ID NOs:24, 66, 66, 66, 66, 70, 70, 70, 58, 62, 78, 74, 46, 46, 42, 54 and 54,respectively, in order of appearance).

FIG. 11 shows exemplary cancers having relatively high proportions ofpatients that are triple-positive for PD-L1/CD8/IFN-γ.

FIG. 12 shows exemplary ER+ breast cancer and pancreatic cancer havingrelatively low proportions for patients that are triple positive forPD-L1/CD8/IFN-γ.

FIG. 13 shows the proportion of exemplary breast cancer patients thatare triple positive for PD-L1/CD8/IFN-γ.

FIG. 14 shows the proportion of exemplary colon cancer patients that aretriple positive for PD-L1/CD8/IFN-γ.

FIG. 15 shows a graphical representation of flow cytometry of PD-L1surface expression in EBC-1 cells in vitro with or without Compound A17treatment. EBC-1 cells are non-small cell lung cancer cells with a cMETamplification.

FIG. 16 shows a graphical representation of PD-L1 mRNA expression inHs.746.T cells in a tumor xenograft model with or without Compound A17treatment. Hs.746.T cells are gastric cancer cells with a c-METamplification and a c-MET mutation.

FIG. 17 shows a graphical representation of PD-L1 mRNA expression inH3122 cells in vitro with or without Compound A23. H3122 cells arenon-small cell lung cancer (NSCLC) cells with an ALK translocation.

FIG. 18 shows a graphical representation of PD-L1 mRNA expression inLOXIMV1 cells (BRAF mutant melanoma cells) in a tumor xenograft modelwith or without Compound A29 treatment.

FIG. 19 shows a graphical representation of PD-L1 mRNA expression inHEYA8 cells (KRAS mutant ovarian cancer cells) in a tumor xenograftmodel with or without Compound A34 treatment.

FIG. 20 shows a graphical representation of PD-L1 mRNA expression inUKE-1 cells (JAK2 V617F mutant myeloproliferative neoplasm cells) in atumor xenograft model with or without Compound A18 treatment.

BRIEF DESCRIPTION OF THE TABLES

Table 1 is a summary of the amino acid and nucleotide sequences for themurine, chimeric and humanized anti-PD-1 antibody molecules. Theantibody molecules include murine mAb BAP049, chimeric mAbs BAP049-chiand BAP049-chi-Y, and humanized mAbs BAP049-hum01 to BAP049-hum16 andBAP049-Clone-A to BAP049-Clone-E. The amino acid and nucleotidesequences of the heavy and light chain CDRs, the amino acid andnucleotide sequences of the heavy and light chain variable regions, andthe amino acid and nucleotide sequences of the heavy and light chainsare shown in this Table.

Table 2 depicts the amino acid and nucleotide sequences of the heavy andlight chain framework regions for humanized mAbs BAP049-hum01 toBAP049-hum16 and BAP049-Clone-A to BAP049-Clone-E.

Table 3 depicts the constant region amino acid sequences of human IgGheavy chains and human kappa light chain.

Table 4 shows the amino acid sequences of the heavy and light chainleader sequences for humanized mAbs BAP049-Clone-A to BAP049-Clone-E.

Table 5 is a summary of yield, titre, monomer content and endotoxinlevels for selected humanized BAP049 mAbs expressed in CHO cells.

Table 6 shows the charge isoforms as detected by Novex IEF analysis forselected humanized BAP049 mAbs expressed in CHO cells.

Table 7 is a summary of selected therapeutic agents that can beadministered in combination with the anti-PD-1 antibody molecules andother immunomodulators (e.g., one or more of: an activator of acostimulatory molecule and/or an inhibitor of an immune checkpointmolecule) described herein. Table 7 provides from left to right thefollowing: the Compound Designation of the second therapeutic agent, theCompound structure, and Patent publication(s) disclosing the Compound.

DETAILED DESCRIPTION

Programmed Death 1 (PD-1) is a CD28/CTLA-4 family member expressed onactivated CD4⁺ and CD8⁺ T cells, T_(regs), and B cells. It negativelyregulates effector T cell signaling and function. PD-1 is induced ontumor-infiltrating T cells, resulting in functional exhaustion ordysfunction (Keir et al. (2008) Annu. Rev. Immunol. 26:677-704; Pardollet al. (2012) Nat Rev Cancer 12(4):252-64).

PD-1 delivers a coinhibitory signal upon binding to either of its twoligands, Programmed Death-Ligand 1 (PD-L1) or Programmed Death-Ligand 2(PD-L2). PD-L1 is expressed on T cells, natural killer (NK) cells,macrophages, dendritic cells (DCs), B cells, epithelial cells, vascularendothelial cells, as well as many types of tumors. High expression ofPD-L1 on murine and human tumors has been linked to poor clinicaloutcomes in a variety of cancers (Keir et al. (2008) Annu. Rev. Immunol.26:677-704; Pardoll et al. (2012) Nat Rev Cancer 12(4):252-64). PD-L2 isexpressed on dendritic cells, macrophages, and some tumors.

Blockade of the PD-1 pathway has been pre-clinically and clinicallyvalidated for cancer immunotherapy. Both preclinical and clinicalstudies have demonstrated that anti-PD-1 blockade restores activity ofeffector T cells and results in robust anti-tumor response. For example,blockade of PD-1 pathway restores exhausted/dysfunctional effector Tcell function (e.g., proliferation, IFN-γ secretion, or cytolyticfunction) and inhibits T_(reg) cell function (Keir et al. (2008) Annu.Rev. Immunol. 26:677-704; Pardoll et al. (2012) Nat Rev Cancer12(4):252-64).

Accordingly, the present invention provides, at least in part, antibodymolecules (e.g., humanized antibody molecules) that bind to ProgrammedDeath 1 (PD-1) with high affinity and specificity. In one embodiment,humanized antibodies against PD-1 are disclosed, which show asurprisingly low immunogenicity. For example, humanized BAP049antibodies were found to have a risk score of less than 650, 600, 550,or less than 500, according to the T cell epitope assays describedherein. In other embodiments, selected combination of framework regions,e.g., as shown in FIGS. 5 and 7, were shown to have distinct productionefficiencies and binding properties.

Additional aspects of the invention include nucleic acid moleculesencoding the antibody molecules, expression vectors, host cells andmethods for making the antibody molecules. Immunoconjugates, multi- orbispecific molecules and pharmaceutical compositions comprising theantibody molecules are also provided. The anti-PD-1 antibody moleculesdisclosed herein can be used to treat, prevent and/or diagnose cancerousor malignant disorders (e.g., solid and soft-tissue tumors; melanoma,e.g., advanced melanoma; hepatocellular carcinoma; pancreatic cancer;renal cell carcinoma (RCC), e.g., metastatic RCC or clear cell RCC;gliomas or glioblastomas; multiple myeloma; colorectal cancer; and lungcancer, e.g., non-small cell carcinoma), as well as infectious diseases(e.g., infectious disorders such as hepatitis, e.g., hepatitis C (e.g.,chronic viral hepatitis); sepsis). Thus, methods for detecting PD-1, aswell as methods for treating various disorders, including cancer andinfectious diseases using the anti-PD-1 antibody molecules are disclosedherein.

The term “Programmed Death 1” or “PD-1” include isoforms, mammalian,e.g., human PD-1, species homologs of human PD-1, and analogs comprisingat least one common epitope with PD-1. The amino acid sequence of PD-1,e.g., human PD-1, is known in the art, e.g., Shinohara T et al. (1994)Genomics 23(3):704-6; Finger L R, et al. Gene (1997) 197(1-2):177-87.

Additional terms are defined below and throughout the application.

As used herein, the articles “a” and “an” refer to one or to more thanone (e.g., to at least one) of the grammatical object of the article.

The term “or” is used herein to mean, and is used interchangeably with,the term “and/or”, unless context clearly indicates otherwise.

“About” and “approximately” shall generally mean an acceptable degree oferror for the quantity measured given the nature or precision of themeasurements. Exemplary degrees of error are within 20 percent (%),typically, within 10%, and more typically, within 5% of a given value orrange of values.

The compositions and methods of the present invention encompasspolypeptides and nucleic acids having the sequences specified, orsequences substantially identical or similar thereto, e.g., sequences atleast 85%, 90%, 95% identical or higher to the sequence specified. Inthe context of an amino acid sequence, the term “substantiallyidentical” is used herein to refer to a first amino acid that contains asufficient or minimum number of amino acid residues that are i)identical to, or ii) conservative substitutions of aligned amino acidresidues in a second amino acid sequence such that the first and secondamino acid sequences can have a common structural domain and/or commonfunctional activity. For example, amino acid sequences that contain acommon structural domain having at least about 85%, 90%. 91%, 92%, 93%,94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence, e.g., asequence provided herein.

In the context of nucleotide sequence, the term “substantiallyidentical” is used herein to refer to a first nucleic acid sequence thatcontains a sufficient or minimum number of nucleotides that areidentical to aligned nucleotides in a second nucleic acid sequence suchthat the first and second nucleotide sequences encode a polypeptidehaving common functional activity, or encode a common structuralpolypeptide domain or a common functional polypeptide activity. Forexample, nucleotide sequences having at least about 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% identity to a reference sequence,e.g., a sequence provided herein.

The term “functional variant” refers to polypeptides that have asubstantially identical amino acid sequence to the naturally-occurringsequence, or are encoded by a substantially identical nucleotidesequence, and are capable of having one or more activities of thenaturally-occurring sequence.

Calculations of homology or sequence identity between sequences (theterms are used interchangeably herein) are performed as follows.

To determine the percent identity of two amino acid sequences, or of twonucleic acid sequences, the sequences are aligned for optimal comparisonpurposes (e.g., gaps can be introduced in one or both of a first and asecond amino acid or nucleic acid sequence for optimal alignment andnon-homologous sequences can be disregarded for comparison purposes). Ina preferred embodiment, the length of a reference sequence aligned forcomparison purposes is at least 30%, preferably at least 40%, morepreferably at least 50%, 60%, and even more preferably at least 70%,80%, 90%, 100% of the length of the reference sequence. The amino acidresidues or nucleotides at corresponding amino acid positions ornucleotide positions are then compared. When a position in the firstsequence is occupied by the same amino acid residue or nucleotide as thecorresponding position in the second sequence, then the molecules areidentical at that position (as used herein amino acid or nucleic acid“identity” is equivalent to amino acid or nucleic acid “homology”).

The percent identity between the two sequences is a function of thenumber of identical positions shared by the sequences, taking intoaccount the number of gaps, and the length of each gap, which need to beintroduced for optimal alignment of the two sequences.

The comparison of sequences and determination of percent identitybetween two sequences can be accomplished using a mathematicalalgorithm. In a preferred embodiment, the percent identity between twoamino acid sequences is determined using the Needleman and Wunsch((1970) J. Mol. Biol. 48:444-453) algorithm which has been incorporatedinto the GAP program in the GCG software package (available athttp://www.gcg.com), using either a Blossum 62 matrix or a PAM250matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a lengthweight of 1, 2, 3, 4, 5, or 6. In yet another preferred embodiment, thepercent identity between two nucleotide sequences is determined usingthe GAP program in the GCG software package (available athttp://www.gcg.com), using a NWSgapdna.CMP matrix and a gap weight of40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. Aparticularly preferred set of parameters (and the one that should beused unless otherwise specified) are a Blossum 62 scoring matrix with agap penalty of 12, a gap extend penalty of 4, and a frameshift gappenalty of 5.

The percent identity between two amino acid or nucleotide sequences canbe determined using the algorithm of E. Meyers and W. Miller ((1989)CABIOS, 4:11-17) which has been incorporated into the ALIGN program(version 2.0), using a PAM120 weight residue table, a gap length penaltyof 12 and a gap penalty of 4.

The nucleic acid and protein sequences described herein can be used as a“query sequence” to perform a search against public databases to, forexample, identify other family members or related sequences. Suchsearches can be performed using the NBLAST and XBLAST programs (version2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLASTnucleotide searches can be performed with the NBLAST program, score=100,wordlength=12 to obtain nucleotide sequences homologous to a nucleicacid (SEQ ID NO: 1) molecules of the invention. BLAST protein searchescan be performed with the XBLAST program, score=50, wordlength=3 toobtain amino acid sequences homologous to protein molecules of theinvention. To obtain gapped alignments for comparison purposes, GappedBLAST can be utilized as described in Altschul et al., (1997) NucleicAcids Res. 25:3389-3402. When utilizing BLAST and Gapped BLAST programs,the default parameters of the respective programs (e.g., XBLAST andNBLAST) can be used. See http://www.ncbi.nlm.nih.gov.

As used herein, the term “hybridizes under low stringency, mediumstringency, high stringency, or very high stringency conditions”describes conditions for hybridization and washing. Guidance forperforming hybridization reactions can be found in Current Protocols inMolecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6, which isincorporated by reference. Aqueous and nonaqueous methods are describedin that reference and either can be used. Specific hybridizationconditions referred to herein are as follows: 1) low stringencyhybridization conditions in 6× sodium chloride/sodium citrate (SSC) atabout 45° C., followed by two washes in 0.2×SSC, 0.1% SDS at least at50° C. (the temperature of the washes can be increased to 55° C. for lowstringency conditions); 2) medium stringency hybridization conditions in6×SSC at about 45° C., followed by one or more washes in 0.2×SSC, 0.1%SDS at 60° C.; 3) high stringency hybridization conditions in 6×SSC atabout 45° C., followed by one or more washes in 0.2×SSC, 0.1% SDS at 65°C.; and preferably 4) very high stringency hybridization conditions are0.5M sodium phosphate, 7% SDS at 65° C., followed by one or more washesat 0.2×SSC, 1% SDS at 65° C. Very high stringency conditions (4) are thepreferred conditions and the ones that should be used unless otherwisespecified.

It is understood that the molecules of the present invention may haveadditional conservative or non-essential amino acid substitutions, whichdo not have a substantial effect on their functions.

The term “amino acid” is intended to embrace all molecules, whethernatural or synthetic, which include both an amino functionality and anacid functionality and capable of being included in a polymer ofnaturally-occurring amino acids. Exemplary amino acids includenaturally-occurring amino acids; analogs, derivatives and congenersthereof; amino acid analogs having variant side chains; and allstereoisomers of any of any of the foregoing. As used herein the term“amino acid” includes both the D- or L-optical isomers andpeptidomimetics.

A “conservative amino acid substitution” is one in which the amino acidresidue is replaced with an amino acid residue having a similar sidechain. Families of amino acid residues having similar side chains havebeen defined in the art. These families include amino acids with basicside chains (e.g., lysine, arginine, histidine), acidic side chains(e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g.,glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine),nonpolar side chains (e.g., alanine, valine, leucine, isoleucine,proline, phenylalanine, methionine, tryptophan), beta-branched sidechains (e.g., threonine, valine, isoleucine) and aromatic side chains(e.g., tyrosine, phenylalanine, tryptophan, histidine).

The terms “polypeptide”, “peptide” and “protein” (if single chain) areused interchangeably herein to refer to polymers of amino acids of anylength. The polymer may be linear or branched, it may comprise modifiedamino acids, and it may be interrupted by non-amino acids. The termsalso encompass an amino acid polymer that has been modified; forexample, disulfide bond formation, glycosylation, lipidation,acetylation, phosphorylation, or any other manipulation, such asconjugation with a labeling component. The polypeptide can be isolatedfrom natural sources, can be a produced by recombinant techniques from aeukaryotic or prokaryotic host, or can be a product of syntheticprocedures.

The terms “nucleic acid,” “nucleic acid sequence,” “nucleotidesequence,” or “polynucleotide sequence,” and “polynucleotide” are usedinterchangeably. They refer to a polymeric form of nucleotides of anylength, either deoxyribonucleotides or ribonucleotides, or analogsthereof. The polynucleotide may be either single-stranded ordouble-stranded, and if single-stranded may be the coding strand ornon-coding (antisense) strand. A polynucleotide may comprise modifiednucleotides, such as methylated nucleotides and nucleotide analogs. Thesequence of nucleotides may be interrupted by non-nucleotide components.A polynucleotide may be further modified after polymerization, such asby conjugation with a labeling component. The nucleic acid may be arecombinant polynucleotide, or a polynucleotide of genomic, cDNA,semisynthetic, or synthetic origin which either does not occur in natureor is linked to another polynucleotide in a nonnatural arrangement.

The term “isolated,” as used herein, refers to material that is removedfrom its original or native environment (e.g., the natural environmentif it is naturally occurring). For example, a naturally-occurringpolynucleotide or polypeptide present in a living animal is notisolated, but the same polynucleotide or polypeptide, separated by humanintervention from some or all of the co-existing materials in thenatural system, is isolated. Such polynucleotides could be part of avector and/or such polynucleotides or polypeptides could be part of acomposition, and still be isolated in that such vector or composition isnot part of the environment in which it is found in nature.

Various aspects of the invention are described in further detail below.Additional definitions are set out throughout the specification.

Antibody Molecules

In one embodiment, the antibody molecule binds to a mammalian, e.g.,human, PD-1. For example, the antibody molecule binds specifically to anepitope, e.g., linear or conformational epitope, (e.g., an epitope asdescribed herein) on PD-1.

As used herein, the term “antibody molecule” refers to a protein, e.g.,an immunoglobulin chain or fragment thereof, comprising at least oneimmunoglobulin variable domain sequence. The term “antibody molecule”includes, for example, a monoclonal antibody (including a full lengthantibody which has an immunoglobulin Fc region). In an embodiment, anantibody molecule comprises a full length antibody, or a full lengthimmunoglobulin chain. In an embodiment, an antibody molecule comprisesan antigen binding or functional fragment of a full length antibody, ora full length immunoglobulin chain.

In an embodiment, an antibody molecule is a monospecific antibodymolecule and binds a single epitope. E.g., a monospecific antibodymolecule having a plurality of immunoglobulin variable domain sequences,each of which binds the same epitope.

In an embodiment an antibody molecule is a multispecific antibodymolecule, e.g., it comprises a plurality of immunoglobulin variabledomains sequences, wherein a first immunoglobulin variable domainsequence of the plurality has binding specificity for a first epitopeand a second immunoglobulin variable domain sequence of the pluralityhas binding specificity for a second epitope. In an embodiment the firstand second epitopes are on the same antigen, e.g., the same protein (orsubunit of a multimeric protein). In an embodiment the first and secondepitopes overlap. In an embodiment the first and second epitopes do notoverlap. In an embodiment the first and second epitopes are on differentantigens, e.g., the different proteins (or different subunits of amultimeric protein). In an embodiment a multispecific antibody moleculecomprises a third, fourth or fifth immunoglobulin variable domain. In anembodiment, a multispecific antibody molecule is a bispecific antibodymolecule, a trispecific antibody molecule, or tetraspecific antibodymolecule,

In an embodiment a multispecific antibody molecule is a bispecificantibody molecule. A bispecific antibody has specificity for no morethan two antigens. A bispecific antibody molecule is characterized by afirst immunoglobulin variable domain sequence which has bindingspecificity for a first epitope and a second immunoglobulin variabledomain sequence that has binding specificity for a second epitope. In anembodiment the first and second epitopes are on the same antigen, e.g.,the same protein (or subunit of a multimeric protein). In an embodimentthe first and second epitopes overlap. In an embodiment the first andsecond epitopes do not overlap. In an embodiment the first and secondepitopes are on different antigens, e.g., the different proteins (ordifferent subunits of a multimeric protein). In an embodiment abispecific antibody molecule comprises a heavy chain variable domainsequence and a light chain variable domain sequence which have bindingspecificity for a first epitope and a heavy chain variable domainsequence and a light chain variable domain sequence which have bindingspecificity for a second epitope. In an embodiment a bispecific antibodymolecule comprises a half antibody having binding specificity for afirst epitope and a half antibody having binding specificity for asecond epitope. In an embodiment a bispecific antibody moleculecomprises a half antibody, or fragment thereof, having bindingspecificity for a first epitope and a half antibody, or fragmentthereof, having binding specificity for a second epitope. In anembodiment a bispecific antibody molecule comprises a scFv, or fragmentthereof, have binding specificity for a first epitope and a scFv, orfragment thereof, have binding specificity for a second epitope. In anembodiment the first epitope is located on PD-1 and the second epitopeis located on a TIM-3, LAG-3, CEACAM (e.g., CEACAM-1 and/or CEACAM-5),PD-L1, or PD-L2.

In an embodiment, an antibody molecule comprises a diabody, and asingle-chain molecule, as well as an antigen-binding fragment of anantibody (e.g., Fab, F(ab′)₂, and Fv). For example, an antibody moleculecan include a heavy (H) chain variable domain sequence (abbreviatedherein as VH), and a light (L) chain variable domain sequence(abbreviated herein as VL). In an embodiment an antibody moleculecomprises or consists of a heavy chain and a light chain (referred toherein as a half antibody. In another example, an antibody moleculeincludes two heavy (H) chain variable domain sequences and two light (L)chain variable domain sequence, thereby forming two antigen bindingsites, such as Fab, Fab′, F(ab′)₂, Fc, Fd, Fd′, Fv, single chainantibodies (scFv for example), single variable domain antibodies,diabodies (Dab) (bivalent and bispecific), and chimeric (e.g.,humanized) antibodies, which may be produced by the modification ofwhole antibodies or those synthesized de novo using recombinant DNAtechnologies. These functional antibody fragments retain the ability toselectively bind with their respective antigen or receptor. Antibodiesand antibody fragments can be from any class of antibodies including,but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass(e.g., IgG1, IgG2, IgG3, and IgG4) of antibodies. The a preparation ofantibody molecules can be monoclonal or polyclonal. An antibodymoleculecan also be a human, humanized, CDR-grafted, or in vitro generatedantibody. The antibody can have a heavy chain constant region chosenfrom, e.g., IgG1, IgG2, IgG3, or IgG4. The antibody can also have alight chain chosen from, e.g., kappa or lambda. The term“immunoglobulin” (Ig) is used interchangeably with the term “antibody”herein.

Examples of antigen-binding fragments of an antibody molecule include:(i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CLand CH1 domains; (ii) a F(ab′)2 fragment, a bivalent fragment comprisingtwo Fab fragments linked by a disulfide bridge at the hinge region;(iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fvfragment consisting of the VL and VH domains of a single arm of anantibody, (v) a diabody (dAb) fragment, which consists of a VH domain;(vi) a camelid or camelized variable domain; (vii) a single chain Fv(scFv), see e.g., Bird et al. (1988) Science 242:423-426; and Huston etal. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); (viii) a singledomain antibody. These antibody fragments are obtained usingconventional techniques known to those with skill in the art, and thefragments are screened for utility in the same manner as are intactantibodies.

The term “antibody” includes intact molecules as well as functionalfragments thereof. Constant regions of the antibodies can be altered,e.g., mutated, to modify the properties of the antibody (e.g., toincrease or decrease one or more of: Fc receptor binding, antibodyglycosylation, the number of cysteine residues, effector cell function,or complement function).

Antibody molecules can also be single domain antibodies. Single domainantibodies can include antibodies whose complementary determiningregions are part of a single domain polypeptide. Examples include, butare not limited to, heavy chain antibodies, antibodies naturally devoidof light chains, single domain antibodies derived from conventional4-chain antibodies, engineered antibodies and single domain scaffoldsother than those derived from antibodies. Single domain antibodies maybe any of the art, or any future single domain antibodies. Single domainantibodies may be derived from any species including, but not limited tomouse, human, camel, llama, fish, shark, goat, rabbit, and bovine.According to another aspect of the invention, a single domain antibodyis a naturally occurring single domain antibody known as heavy chainantibody devoid of light chains. Such single domain antibodies aredisclosed in WO 9404678, for example. For clarity reasons, this variabledomain derived from a heavy chain antibody naturally devoid of lightchain is known herein as a VHH or nanobody to distinguish it from theconventional VH of four chain immunoglobulins. Such a VHH molecule canbe derived from antibodies raised in Camelidae species, for example incamel, llama, dromedary, alpaca and guanaco. Other species besidesCamelidae may produce heavy chain antibodies naturally devoid of lightchain; such VHHs are within the scope of the invention.

The VH and VL regions can be subdivided into regions ofhypervariability, termed “complementarity determining regions” (CDR),interspersed with regions that are more conserved, termed “frameworkregions” (FR or FW).

The extent of the framework region and CDRs has been precisely definedby a number of methods (see, Kabat, E. A., et al. (1991) Sequences ofProteins of Immunological Interest, Fifth Edition, U.S. Department ofHealth and Human Services, NIH Publication No. 91-3242; Chothia, C. etal. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used byOxford Molecular's AbM antibody modeling software. See, generally, e.g.,Protein Sequence and Structure Analysis of Antibody Variable Domains.In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R.,Springer-Verlag, Heidelberg).

The terms “complementarity determining region,” and “CDR,” as usedherein refer to the sequences of amino acids within antibody variableregions which confer antigen specificity and binding affinity. Ingeneral, there are three CDRs in each heavy chain variable region(HCDR1, HCDR2, HCDR3) and three CDRs in each light chain variable region(LCDR1, LCDR2, LCDR3).

The precise amino acid sequence boundaries of a given CDR can bedetermined using any of a number of well-known schemes, including thosedescribed by Kabat et al. (1991), “Sequences of Proteins ofImmunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (“Kabat” numbering scheme),Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme).As used herein, the CDRs defined according the “Chothia” number schemeare also sometimes referred to as “hypervariable loops.”

For example, under Kabat, the CDR amino acid residues in the heavy chainvariable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3); and the CDR amino acid residues in the light chainvariable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and89-97 (LCDR3). Under Chothia the CDR amino acids in the VH are numbered26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acidresidues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96(LCDR3). By combining the CDR definitions of both Kabat and Chothia, theCDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and95-102 (HCDR3) in human VH and amino acid residues 24-34 (LCDR1), 50-56(LCDR2), and 89-97 (LCDR3) in human VL.

Generally, unless specifically indicated, the anti-PD-1 antibodymolecules can include any combination of one or more Kabat CDRs and/orChothia hypervariable loops, e.g., described in Table 1. In oneembodiment, the following definitions are used for the anti-PD-1antibody molecules described in Table 1: HCDR1 according to the combinedCDR definitions of both Kabat and Chothia, and HCCDRs 2-3 and LCCDRs 1-3according the CDR definition of Kabat. Under all definitions, each VHand VL typically includes three CDRs and four FRs, arranged fromamino-terminus to carboxy-terminus in the following order: FR1, CDR1,FR2, CDR2, FR3, CDR3, FR4.

As used herein, an “immunoglobulin variable domain sequence” refers toan amino acid sequence which can form the structure of an immunoglobulinvariable domain. For example, the sequence may include all or part ofthe amino acid sequence of a naturally-occurring variable domain. Forexample, the sequence may or may not include one, two, or more N- orC-terminal amino acids, or may include other alterations that arecompatible with formation of the protein structure.

The term “antigen-binding site” refers to the part of an antibodymolecule that comprises determinants that form an interface that bindsto the PD-1 polypeptide, or an epitope thereof. With respect to proteins(or protein mimetics), the antigen-binding site typically includes oneor more loops (of at least four amino acids or amino acid mimics) thatform an interface that binds to the PD-1 polypeptide. Typically, theantigen-binding site of an antibody molecule includes at least one ortwo CDRs and/or hypervariable loops, or more typically at least three,four, five or six CDRs and/or hypervariable loops.

The terms “compete” or “cross-compete” are used interchangeably hereinto refer to the ability of an antibody molecule to interfere withbinding of an anti-PD-1 antibody molecule, e.g., an anti-PD-1 antibodymolecule provided herein, to a target, e.g., human PD-1. Theinterference with binding can be direct or indirect (e.g., through anallosteric modulation of the antibody molecule or the target). Theextent to which an antibody molecule is able to interfere with thebinding of another antibody molecule to the target, and thereforewhether it can be said to compete, can be determined using a competitionbinding assay, for example, a FACS assay, an ELISA or BIACORE assay. Insome embodiments, a competition binding assay is a quantitativecompetition assay. In some embodiments, a first anti-PD-1 antibodymolecule is said to compete for binding to the target with a secondanti-PD-1 antibody molecule when the binding of the first antibodymolecule to the target is reduced by 10% or more, e.g., 20% or more, 30%or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% ormore, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more,95% or more, 98% or more, 99% or more in a competition binding assay(e.g., a competition assay described herein).

The terms “monoclonal antibody” or “monoclonal antibody composition” asused herein refer to a preparation of antibody molecules of singlemolecular composition. A monoclonal antibody composition displays asingle binding specificity and affinity for a particular epitope. Amonoclonal antibody can be made by hybridoma technology or by methodsthat do not use hybridoma technology (e.g., recombinant methods).

An “effectively human” protein is a protein that does not evoke aneutralizing antibody response, e.g., the human anti-murine antibody(HAMA) response. HAMA can be problematic in a number of circumstances,e.g., if the antibody molecule is administered repeatedly, e.g., intreatment of a chronic or recurrent disease condition. A HAMA responsecan make repeated antibody administration potentially ineffectivebecause of an increased antibody clearance from the serum (see, e.g.,Saleh et al., Cancer Immunol. Immunother., 32:180-190 (1990)) and alsobecause of potential allergic reactions (see, e.g., LoBuglio et al.,Hybridoma, 5:5117-5123 (1986)).

The antibody molecule can be a polyclonal or a monoclonal antibody. Inother embodiments, the antibody can be recombinantly produced, e.g.,produced by phage display or by combinatorial methods.

Phage display and combinatorial methods for generating antibodies areknown in the art (as described in, e.g., Ladner et al. U.S. Pat. No.5,223,409; Kang et al. International Publication No. WO 92/18619; Doweret al. International Publication No. WO 91/17271; Winter et al.International Publication WO 92/20791; Markland et al. InternationalPublication No. WO 92/15679; Breitling et al. International PublicationWO 93/01288; McCafferty et al. International Publication No. WO92/01047; Garrard et al. International Publication No. WO 92/09690;Ladner et al. International Publication No. WO 90/02809; Fuchs et al.(1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum AntibodHybridomas 3:81-85; Huse et al. (1989) Science 246:1275-1281; Griffthset al. (1993) EMBO J 12:725-734; Hawkins et al. (1992) J Mol Biol226:889-896; Clackson et al. (1991) Nature 352:624-628; Gram et al.(1992) PNAS 89:3576-3580; Garrad et al. (1991) Bio/Technology9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:4133-4137; andBarbas et al. (1991) PNAS 88:7978-7982, the contents of all of which areincorporated by reference herein).

In one embodiment, the antibody is a fully human antibody (e.g., anantibody made in a mouse which has been genetically engineered toproduce an antibody from a human immunoglobulin sequence), or anon-human antibody, e.g., a rodent (mouse or rat), goat, primate (e.g.,monkey), camel antibody. Preferably, the non-human antibody is a rodent(mouse or rat antibody). Methods of producing rodent antibodies areknown in the art.

Human monoclonal antibodies can be generated using transgenic micecarrying the human immunoglobulin genes rather than the mouse system.Splenocytes from these transgenic mice immunized with the antigen ofinterest are used to produce hybridomas that secrete human mAbs withspecific affinities for epitopes from a human protein (see, e.g., Woodet al.

International Application WO 91/00906, Kucherlapati et al. PCTpublication WO 91/10741; Lonberg et al. International Application WO92/03918; Kay et al. International Application 92/03917; Lonberg, N. etal. 1994 Nature 368:856-859; Green, L. L. et al. 1994 Nature Genet.7:13-21; Morrison, S. L. et al. 1994 Proc. Natl. Acad. Sci. USA81:6851-6855; Bruggeman et al. 1993 Year Immunol 7:33-40; Tuaillon etal. 1993 PNAS 90:3720-3724; Bruggeman et al. 1991 Eur J Immunol21:1323-1326).

An antibody can be one in which the variable region, or a portionthereof, e.g., the CDRs, are generated in a non-human organism, e.g., arat or mouse. Chimeric, CDR-grafted, and humanized antibodies are withinthe invention. Antibodies generated in a non-human organism, e.g., a rator mouse, and then modified, e.g., in the variable framework or constantregion, to decrease antigenicity in a human are within the invention.

Chimeric antibodies can be produced by recombinant DNA techniques knownin the art (see Robinson et al., International Patent PublicationPCT/US86/02269; Akira, et al., European Patent Application 184,187;Taniguchi, M., European Patent Application 171,496; Morrison et al.,European Patent Application 173,494; Neuberger et al., InternationalApplication WO 86/01533; Cabilly et al. U.S. Pat. No. 4,816,567; Cabillyet al., European Patent Application 125,023; Better et al. (1988 Science240:1041-1043); Liu et al. (1987) PNAS 84:3439-3443; Liu et al., 1987,J. Immunol. 139:3521-3526; Sun et al. (1987) PNAS 84:214-218; Nishimuraet al., 1987, Canc. Res. 47:999-1005; Wood et al. (1985) Nature314:446-449; and Shaw et al., 1988, J. Natl Cancer Inst. 80:1553-1559).

A humanized or CDR-grafted antibody will have at least one or two butgenerally all three recipient CDRs (of heavy and or light immuoglobulinchains) replaced with a donor CDR. The antibody may be replaced with atleast a portion of a non-human CDR or only some of the CDRs may bereplaced with non-human CDRs. It is only necessary to replace the numberof CDRs required for binding of the humanized antibody to PD-1.Preferably, the donor will be a rodent antibody, e.g., a rat or mouseantibody, and the recipient will be a human framework or a humanconsensus framework. Typically, the immunoglobulin providing the CDRs iscalled the “donor” and the immunoglobulin providing the framework iscalled the “acceptor.” In one embodiment, the donor immunoglobulin is anon-human (e.g., rodent). The acceptor framework is anaturally-occurring (e.g., a human) framework or a consensus framework,or a sequence about 85% or higher, preferably 90%, 95%, 99% or higheridentical thereto.

As used herein, the term “consensus sequence” refers to the sequenceformed from the most frequently occurring amino acids (or nucleotides)in a family of related sequences (See e.g., Winnaker, From Genes toClones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family ofproteins, each position in the consensus sequence is occupied by theamino acid occurring most frequently at that position in the family. Iftwo amino acids occur equally frequently, either can be included in theconsensus sequence. A “consensus framework” refers to the frameworkregion in the consensus immunoglobulin sequence.

An antibody can be humanized by methods known in the art (see e.g.,Morrison, S. L., 1985, Science 229:1202-1207, by Oi et al., 1986,BioTechniques 4:214, and by Queen et al. U.S. Pat. No. 5,585,089, U.S.Pat. No. 5,693,761 and U.S. Pat. No. 5,693,762, the contents of all ofwhich are hereby incorporated by reference).

Humanized or CDR-grafted antibodies can be produced by CDR-grafting orCDR substitution, wherein one, two, or all CDRs of an immunoglobulinchain can be replaced. See e.g., U.S. Pat. No. 5,225,539; Jones et al.1986 Nature 321:552-525; Verhoeyan et al. 1988 Science 239:1534; Beidleret al. 1988 J. Immunol. 141:4053-4060; Winter U.S. Pat. No. 5,225,539,the contents of all of which are hereby expressly incorporated byreference. Winter describes a CDR-grafting method which may be used toprepare the humanized antibodies of the present invention (UK PatentApplication GB 2188638A, filed on Mar. 26, 1987; Winter U.S. Pat. No.5,225,539), the contents of which is expressly incorporated byreference.

Also within the scope of the invention are humanized antibodies in whichspecific amino acids have been substituted, deleted or added. Criteriafor selecting amino acids from the donor are described in U.S. Pat. No.5,585,089, e.g., columns 12-16 of U.S. Pat. No. 5,585,089, e.g., columns12-16 of U.S. Pat. No. 5,585,089, the contents of which are herebyincorporated by reference. Other techniques for humanizing antibodiesare described in Padlan et al. EP 519596 A1, published on Dec. 23, 1992.

The antibody molecule can be a single chain antibody. A single-chainantibody (scFV) may be engineered (see, for example, Colcher, D. et al.(1999) Ann N Y Acad Sci 880:263-80; and Reiter, Y. (1996) Clin CancerRes 2:245-52). The single chain antibody can be dimerized ormultimerized to generate multivalent antibodies having specificities fordifferent epitopes of the same target protein.

In yet other embodiments, the antibody molecule has a heavy chainconstant region chosen from, e.g., the heavy chain constant regions ofIgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; particularly,chosen from, e.g., the (e.g., human) heavy chain constant regions ofIgG1, IgG2, IgG3, and IgG4. In another embodiment, the antibody moleculehas a light chain constant region chosen from, e.g., the (e.g., human)light chain constant regions of kappa or lambda. The constant region canbe altered, e.g., mutated, to modify the properties of the antibody(e.g., to increase or decrease one or more of: Fc receptor binding,antibody glycosylation, the number of cysteine residues, effector cellfunction, and/or complement function). In one embodiment the antibodyhas: effector function; and can fix complement. In other embodiments theantibody does not; recruit effector cells; or fix complement. In anotherembodiment, the antibody has reduced or no ability to bind an Fcreceptor. For example, it is a isotype or subtype, fragment or othermutant, which does not support binding to an Fc receptor, e.g., it has amutagenized or deleted Fc receptor binding region.

Methods for altering an antibody constant region are known in the art.Antibodies with altered function, e.g. altered affinity for an effectorligand, such as FcR on a cell, or the C1 component of complement can beproduced by replacing at least one amino acid residue in the constantportion of the antibody with a different residue (see e.g., EP 388,151A1, U.S. Pat. No. 5,624,821 and U.S. Pat. No. 5,648,260, the contents ofall of which are hereby incorporated by reference). Similar type ofalterations could be described which if applied to the murine, or otherspecies immunoglobulin would reduce or eliminate these functions.

An antibody molecule can be derivatized or linked to another functionalmolecule (e.g., another peptide or protein). As used herein, a“derivatized” antibody molecule is one that has been modified. Methodsof derivatization include but are not limited to the addition of afluorescent moiety, a radionucleotide, a toxin, an enzyme or an affinityligand such as biotin. Accordingly, the antibody molecules of theinvention are intended to include derivatized and otherwise modifiedforms of the antibodies described herein, including immunoadhesionmolecules. For example, an antibody molecule can be functionally linked(by chemical coupling, genetic fusion, noncovalent association orotherwise) to one or more other molecular entities, such as anotherantibody (e.g., a bispecific antibody or a diabody), a detectable agent,a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptidethat can mediate association of the antibody or antibody portion withanother molecule (such as a streptavidin core region or a polyhistidinetag).

One type of derivatized antibody molecule is produced by crosslinkingtwo or more antibodies (of the same type or of different types, e.g., tocreate bispecific antibodies). Suitable crosslinkers include those thatare heterobifunctional, having two distinctly reactive groups separatedby an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimideester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkersare available from Pierce Chemical Company, Rockford, Ill.

Useful detectable agents with which an antibody molecule of theinvention may be derivatized (or labeled) to include fluorescentcompounds, various enzymes, prosthetic groups, luminescent materials,bioluminescent materials, fluorescent emitting metal atoms, e.g.,europium (Eu), and other anthanides, and radioactive materials(described below). Exemplary fluorescent detectable agents includefluorescein, fluorescein isothiocyanate, rhodamine,5dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin and thelike. An antibody may also be derivatized with detectable enzymes, suchas alkaline phosphatase, horseradish peroxidase, β-galactosidase,acetylcholinesterase, glucose oxidase and the like. When an antibody isderivatized with a detectable enzyme, it is detected by addingadditional reagents that the enzyme uses to produce a detectablereaction product. For example, when the detectable agent horseradishperoxidase is present, the addition of hydrogen peroxide anddiaminobenzidine leads to a colored reaction product, which isdetectable. An antibody molecule may also be derivatized with aprosthetic group (e.g., streptavidin/biotin and avidin/biotin). Forexample, an antibody may be derivatized with biotin, and detectedthrough indirect measurement of avidin or streptavidin binding. Examplesof suitable fluorescent materials include umbelliferone, fluorescein,fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminefluorescein, dansyl chloride or phycoerythrin; an example of aluminescent material includes luminol; and examples of bioluminescentmaterials include luciferase, luciferin, and aequorin.

Labeled antibody molecule can be used, for example, diagnosticallyand/or experimentally in a number of contexts, including (i) to isolatea predetermined antigen by standard techniques, such as affinitychromatography or immunoprecipitation; (ii) to detect a predeterminedantigen (e.g., in a cellular lysate or cell supernatant) in order toevaluate the abundance and pattern of expression of the protein; (iii)to monitor protein levels in tissue as part of a clinical testingprocedure, e.g., to determine the efficacy of a given treatment regimen.

An antibody molecules may be conjugated to another molecular entity,typically a label or a therapeutic (e.g., a cytotoxic or cytostatic)agent or moiety. Radioactive isotopes can be used in diagnostic ortherapeutic applications. Radioactive isotopes that can be coupled tothe anti-PD-1 antibodies include, but are not limited to α-, β-, orγ-emitters, or β- and γ-emitters. Such radioactive isotopes include, butare not limited to iodine (¹³¹I or ¹²⁵I), yttrium (⁹⁰Y), lutetium(¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine (²¹¹At), rhenium(¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), indium (¹¹¹In), technetium (⁹⁹ mTc),phosphorus (³²P), rhodium (¹⁸⁸Rh), sulfur (³⁵S), carbon (¹⁴C), tritium(³H), chromium (⁵¹Cr), chlorine (³⁶Cl), cobalt (⁵⁷Co or ⁵⁸Co), iron(⁵⁹Fe), selenium (⁷⁵Se), or gallium (⁶⁷Ga). Radioisotopes useful astherapeutic agents include yttrium (⁹⁰Y), lutetium (¹⁷⁷Lu), actinium(²²⁵Ac), praseodymium, astatine (²¹¹At), rhenium (¹⁸⁶Re), bismuth (²¹²Bior ²¹³Bi), and rhodium (¹⁸⁸Rh). Radioisotopes useful as labels, e.g.,for use in diagnostics, include iodine (¹³¹I or ¹²⁵I), indium (¹¹¹ In)technetium (⁹⁹mTc), phosphorus (³²P), carbon (¹⁴C), and tritium (³H), orone or more of the therapeutic isotopes listed above.

The invention provides radiolabeled antibody molecules and methods oflabeling the same. In one embodiment, a method of labeling an antibodymolecule is disclosed. The method includes contacting an antibodymolecule, with a chelating agent, to thereby produce a conjugatedantibody. The conjugated antibody is radiolabeled with a radioisotope,e.g., ¹¹¹Indium, ⁹⁰Yttrium and ¹⁷⁷Lutetium, to thereby produce a labeledantibody molecule.

As is discussed above, the antibody molecule can be conjugated to atherapeutic agent. Therapeutically active radioisotopes have alreadybeen mentioned. Examples of other therapeutic agents include taxol,cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin,etoposide, tenoposide, vincristine, vinblastine, colchicine,doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone,mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids,procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids,e.g., maytansinol (see U.S. Pat. No. 5,208,020), CC-1065 (see U.S. Pat.Nos. 5,475,092, 5,585,499, 5,846, 545) and analogs or homologs thereof.Therapeutic agents include, but are not limited to, antimetabolites(e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine,5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine,thioepa chlorambucil, CC-1065, melphalan, carmustine (BSNU) andlomustine (CCNU), cyclothosphamide, busulfan, dibromomannitol,streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (II) (DDP)cisplatin), anthracyclinies (e.g., daunorubicin (formerly daunomycin)and doxorubicin), antibiotics (e.g., dactinomycin (formerlyactinomycin), bleomycin, mithramycin, and anthramycin (AMC)), andanti-mitotic agents (e.g., vincristine, vinblastine, taxol andmaytansinoids).

In one aspect, the invention features a method of providing a targetbinding molecule that specifically binds to a PD-1 receptor. Forexample, the target binding molecule is an antibody molecule. The methodincludes: providing a target protein that comprises at least a portionof non-human protein, the portion being homologous to (at least 70, 75,80, 85, 87, 90, 92, 94, 95, 96, 97, 98% identical to) a correspondingportion of a human target protein, but differing by at least one aminoacid (e.g., at least one, two, three, four, five, six, seven, eight, ornine amino acids); obtaining an antibody molecule that specificallybinds to the antigen; and evaluating efficacy of the binding agent inmodulating activity of the target protein. The method can furtherinclude administering the binding agent (e.g., antibody molecule) or aderivative (e.g., a humanized antibody molecule) to a human subject.

In certain embodiments, the antibody molecule is a multi-specific (e.g.,a bispecific or a trispecific) antibody molecule. Protocols forgenerating bispecific or heterodimeric antibody molecules are known inthe art; including but not limited to, for example, the “knob in a hole”approach described in, e.g., U.S. Pat. No. 5,731,168; the electrostaticsteering Fc pairing as described in, e.g., WO 09/089004, WO 06/106905and WO 2010/129304; Strand Exchange Engineered Domains (SEED)heterodimer formation as described in, e.g., WO 07/110205; Fab armexchange as described in, e.g., WO 08/119353, WO 2011/131746, and WO2013/060867; double antibody conjugate, e.g., by antibody cross-linkingto generate a bi-specific structure using a heterobifunctional reagenthaving an amine-reactive group and a sulfhydryl reactive group asdescribed in, e.g., U.S. Pat. No. 4,433,059; bispecific antibodydeterminants generated by recombining half antibodies (heavy-light chainpairs or Fabs) from different antibodies through cycle of reduction andoxidation of disulfide bonds between the two heavy chains, as describedin, e.g., U.S. Pat. No. 4,444,878; trifunctional antibodies, e.g., threeFab′ fragments cross-linked through sulfhdryl reactive groups, asdescribed in, e.g., U.S. Pat. No. 5,273,743; biosynthetic bindingproteins, e.g., pair of scFvs cross-linked through C-terminal tailspreferably through disulfide or amine-reactive chemical cross-linking,as described in, e.g., U.S. Pat. No. 5,534,254; bifunctional antibodies,e.g., Fab fragments with different binding specificities dimerizedthrough leucine zippers (e.g., c-fos and c-jun) that have replaced theconstant domain, as described in, e.g., U.S. Pat. No. 5,582,996;bispecific and oligospecific mono- and oligovalent receptors, e.g.,VH—CH1 regions of two antibodies (two Fab fragments) linked through apolypeptide spacer between the CH1 region of one antibody and the VHregion of the other antibody typically with associated light chains, asdescribed in, e.g., U.S. Pat. No. 5,591,828; bispecific DNA-antibodyconjugates, e.g., crosslinking of antibodies or Fab fragments through adouble stranded piece of DNA, as described in, e.g., U.S. Pat. No.5,635,602; bispecific fusion proteins, e.g., an expression constructcontaining two scFvs with a hydrophilic helical peptide linker betweenthem and a full constant region, as described in, e.g., U.S. Pat. No.5,637,481; multivalent and multispecific binding proteins, e.g., dimerof polypeptides having first domain with binding region of Ig heavychain variable region, and second domain with binding region of Ig lightchain variable region, generally termed diabodies (higher orderstructures are also disclosed creating bispecifc, trispecific, ortetraspecific molecules, as described in, e.g., U.S. Pat. No. 5,837,242;minibody constructs with linked VL and VH chains further connected withpeptide spacers to an antibody hinge region and CH3 region, which can bedimerized to form bispecific/multivalent molecules, as described in,e.g., U.S. Pat. No. 5,837,821; VH and VL domains linked with a shortpeptide linker (e.g., 5 or 10 amino acids) or no linker at all in eitherorientation, which can form dimers to form bispecific diabodies; trimersand tetramers, as described in, e.g., U.S. Pat. No. 5,844,094; String ofVH domains (or VL domains in family members) connected by peptidelinkages with crosslinkable groups at the C-terminus further associatedwith VL domains to form a series of FVs (or scFvs), as described in,e.g., U.S. Pat. No. 5,864,019; and single chain binding polypeptideswith both a VH and a VL domain linked through a peptide linker arecombined into multivalent structures through non-covalent or chemicalcrosslinking to form, e.g., homobivalent, heterobivalent, trivalent, andtetravalent structures using both scFV or diabody type format, asdescribed in, e.g., U.S. Pat. No. 5,869,620. Additional exemplarymultispecific and bispecific molecules and methods of making the sameare found, for example, in U.S. Pat. No. 5,910,573, U.S. Pat. No.5,932,448, U.S. Pat. No. 5,959,083, U.S. Pat. No. 5,989,830, U.S. Pat.No. 6,005,079, U.S. Pat. No. 6,239,259, U.S. Pat. No. 6,294,353, U.S.Pat. No. 6,333,396, U.S. Pat. No. 6,476,198, U.S. Pat. No. 6,511,663,U.S. Pat. No. 6,670,453, U.S. Pat. No. 6,743,896, U.S. Pat. No.6,809,185, U.S. Pat. No. 6,833,441, U.S. Pat. No. 7,129,330, U.S. Pat.No. 7,183,076, U.S. Pat. No. 7,521,056, U.S. Pat. No. 7,527,787, U.S.Pat. No. 7,534,866, U.S. Pat. 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The contents of theabove-referenced applications are incorporated herein by reference intheir entireties.

In other embodiments, the anti-PD-1 antibody molecule (e.g., amonospecific, bispecific, or multispecific antibody molecule) iscovalently linked, e.g., fused, to another partner e.g., a protein e.g.,one, two or more cytokines, e.g., as a fusion molecule for example afusion protein.

In other embodiments, the fusion molecule comprises one or moreproteins, e.g., one, two or more cytokines. In one embodiment, thecytokine is an interleukin (IL) chosen from one, two, three or more ofIL-1, IL-2, IL-12, IL-15 or IL-21. In one embodiment, a bispecificantibody molecule has a first binding specificity to a first target(e.g., to PD-1), a second binding specificity to a second target (e.g.,LAG-3 or TIM-3), and is optionally linked to an interleukin (e.g.,IL-12) domain e.g., full length IL-12 or a portion thereof.

A “fusion protein” and a “fusion polypeptide” refer to a polypeptidehaving at least two portions covalently linked together, where each ofthe portions is a polypeptide having a different property. The propertymay be a biological property, such as activity in vitro or in vivo. Theproperty can also be simple chemical or physical property, such asbinding to a target molecule, catalysis of a reaction, etc. The twoportions can be linked directly by a single peptide bond or through apeptide linker, but are in reading frame with each other.

This invention provides an isolated nucleic acid molecule encoding theabove antibody molecule, vectors and host cells thereof. The nucleicacid molecule includes but is not limited to RNA, genomic DNA and cDNA.

Exemplary Anti-PD-1 Antibody Molecules

In one embodiment, the anti-PD-1 antibody molecule includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5,and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chainvariable region (VL) comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 33;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO:1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32;

(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or (d) a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO: 32. In certain embodiments, theanti-PD-1 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; aVHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

In other embodiments, the anti-PD-1 antibody molecule comprises:

(i) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence chosen from SEQ ID NO: 1, SEQ ID NO: 4 or SEQ ID NO: 224; aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and

(ii) a light chain variable region (VL) comprising a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.

In embodiments of the aforesaid antibody molecules, the VHCDR1 comprisesthe amino acid sequence of SEQ ID NO: 1. In other embodiments, theVHCDR1 comprises the amino acid sequence of SEQ ID NO: 4. In yet otherembodiments, the VHCDR1 amino acid sequence of SEQ ID NO: 224.

In embodiments, the aforesaid antibody molecules have a heavy chainvariable region comprising at least one framework (FW) region comprisingthe amino acid sequence of any of SEQ ID NOs: 147, 151, 153, 157, 160,162, 166, or 169, or an amino acid sequence at least 90% identicalthereto, or having no more than two amino acid substitutions, insertionsor deletions compared to the amino acid sequence of any of SEQ ID NOs:147, 151, 153, 157, 160, 162, 166, or 169.

In other embodiments, the aforesaid antibody molecules have a heavychain variable region comprising at least one framework regioncomprising the amino acid sequence of any of SEQ ID NOs: 147, 151, 153,157, 160, 162, 166, or 169.

In yet other embodiments, the aforesaid antibody molecules have a heavychain variable region comprising at least two, three, or four frameworkregions comprising the amino acid sequences of any of SEQ ID NOs: 147,151, 153, 157, 160, 162, 166, or 169.

In other embodiments, the aforesaid antibody molecules comprise a VHFW1amino acid sequence of SEQ ID NO: 147 or 151, a VHFW2 amino acidsequence of SEQ ID NO: 153, 157, or 160, and a VHFW3 amino acid sequenceof SEQ ID NO: 162 or 166, and, optionally, further comprising a VHFW4amino acid sequence of SEQ ID NO: 169.

In other embodiments, the aforesaid antibody molecules have a lightchain variable region comprising at least one framework regioncomprising the amino acid sequence of any of SEQ ID NOs: 174, 177, 181,183, 185, 187, 191, 194, 196, 200, 202, 205, or 208, or an amino acidsequence at least 90% identical thereto, or having no more than twoamino acid substitutions, insertions or deletions compared to the aminoacid sequence of any of 174, 177, 181, 183, 185, 187, 191, 194, 196,200, 202, 205, or 208.

In other embodiments, the aforesaid antibody molecules have a lightchain variable region comprising at least one framework regioncomprising the amino acid sequence of any of SEQ ID NOs: 174, 177, 181,183, 185, 187, 191, 194, 196, 200, 202, 205, or 208.

In other embodiments, the aforesaid antibody molecules have a lightchain variable region comprising at least two, three, or four frameworkregions comprising the amino acid sequences of any of SEQ ID NOs: 174,177, 181, 183, 185, 187, 191, 194, 196, 200, 202, 205, or 208.

In other embodiments, the aforesaid antibody molecules comprise a VLFW1amino acid sequence of SEQ ID NO: 174, 177, 181, 183, or 185, a VLFW2amino acid sequence of SEQ ID NO: 187, 191, or 194, and a VLFW3 aminoacid sequence of SEQ ID NO: 196, 200, 202, or 205, and, optionally,further comprising a VLFW4 amino acid sequence of SEQ ID NO: 208.

In other embodiments, the aforesaid antibodies comprise a heavy chainvariable domain comprising an amino acid sequence at least 85% identicalto any of SEQ ID NOs: 38, 50, 82, or 86.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38, 50, 82, or 86.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising an amino acid sequence at least 85%identical to any of SEQ ID NOs: 42, 46, 54, 58, 62, 66, 70, 74, or 78.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:42, 46, 54, 58, 62, 66, 70, 74, or 78.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 91.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:50.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 52 or SEQ ID NO:102.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:82.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 84.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:86.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 88.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:42.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:46.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:54.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:58.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:62.

In other embodiments, the aforesaid antibodies comprise a light chaincomprising the amino acid sequence of SEQ ID NO: 64.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:66.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:70.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:74.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 76.

In other embodiments, the aforesaid antibody molecules comprise a lightchain variable domain comprising the amino acid sequence of SEQ ID NO:78.

In other embodiments, the aforesaid antibody molecules comprise a lightchain comprising the amino acid sequence of SEQ ID NO: 80.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 42.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 66.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 70.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:50 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 70.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 46.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:50 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 46.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:50 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 54.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 54.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 58.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 62.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:50 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 66.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 74.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:38 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 78.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:82 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 70.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:82 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 66.

In other embodiments, the aforesaid antibody molecules comprise a heavychain variable domain comprising the amino acid sequence of SEQ ID NO:86 and a light chain variable domain comprising the amino acid sequenceof SEQ ID NO: 66.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 91 and a lightchain comprising the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 91 and a lightchain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 91 and a lightchain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 91 and a lightchain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 102 and a lightchain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 44.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 52 and a lightchain comprising the amino acid sequence of SEQ ID NO: 48.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 52 and a lightchain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 56.

In other embodiments, the aforesaid antibodies comprise a heavy chaincomprising the amino acid sequence of SEQ ID NO: 40 and a light chaincomprising the amino acid sequence of SEQ ID NO: 60.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 64.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 52 and a lightchain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 52 and a lightchain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 76.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 40 and a lightchain comprising the amino acid sequence of SEQ ID NO: 80.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 84 and a lightchain comprising the amino acid sequence of SEQ ID NO: 72.

In other embodiments, the aforesaid antibodies comprise a heavy chaincomprising the amino acid sequence of SEQ ID NO: 84 and a light chaincomprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforesaid antibody molecules comprise a heavychain comprising the amino acid sequence of SEQ ID NO: 88 and a lightchain comprising the amino acid sequence of SEQ ID NO: 68.

In other embodiments, the aforesaid antibody molecules are chosen from aFab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).

In other embodiments, the aforesaid antibody molecules comprise a heavychain constant region selected from IgG1, IgG2, IgG3, and IgG4.

In other embodiments, the aforesaid antibody molecules comprise a lightchain constant region chosen from the light chain constant regions ofkappa or lambda.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG4 heavy chain constant region with a mutation at position 228according to EU numbering or position 108 of SEQ ID NO: 212 or 214 and akappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG4 heavy chain constant region with a Serine to Proline mutation atposition 228 according to EU numbering or position 108 of SEQ ID NO: 212or 214 and a kappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG1 heavy chain constant region with an Asparagine to Alanine mutationat position 297 according to EU numbering or position 180 of SEQ ID NO:216 and a kappa light chain constant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG1 heavy chain constant region with an Aspartate to Alanine mutationat position 265 according to EU numbering or position 148 of SEQ ID NO:217, and Proline to Alanine mutation at position 329 according to EUnumbering or position 212 of SEQ ID NO: 217 and a kappa light chainconstant region.

In other embodiments, the aforesaid antibody molecules comprise a humanIgG1 heavy chain constant region with a Leucine to Alanine mutation atposition 234 according to EU numbering or position 117 of SEQ ID NO:218, and Leucine to Alanine mutation at position 235 according to EUnumbering or position 118 of SEQ ID NO: 218 and a kappa light chainconstant region.

In other embodiments, the aforesaid antibody molecules are capable ofbinding to human PD-1 with a dissociation constant (K_(D)) of less thanabout 0.2 nM.

In some embodiments, the aforesaid antibody molecules bind to human PD-1with a K_(D) of less than about 0.2 nM, 0.15 nM, 0.1 nM, 0.05 nM, or0.02 nM, e.g., about 0.13 nM to 0.03 nM, e.g., about 0.077 nM to 0.088nM, e.g., about 0.083 nM, e.g., as measured by a Biacore method.

In other embodiments, the aforesaid antibody molecules bind tocynomolgus PD-1 with a K_(D) of less than about 0.2 nM, 0.15 nM, 0.1 nM,0.05 nM, or 0.02 nM, e.g., about 0.11 nM to 0.08 nM, e.g., about 0.093nM, e.g., as measured by a Biacore method.

In certain embodiments, the aforesaid antibody molecules bind to bothhuman PD-1 and cynomolgus PD-1 with similar K_(D), e.g., in the nMrange, e.g., as measured by a Biacore method. In some embodiments, theaforesaid antibody molecules bind to a human PD-1-Ig fusion protein witha K_(D) of less than about 0.1 nM, 0.075 nM, 0.05 nM, 0.025 nM, or 0.01nM, e.g., about 0.04 nM, e.g., as measured by ELISA.

In some embodiments, the aforesaid antibody molecules bind to Jurkatcells that express human PD-1 (e.g., human PD-1-transfected Jurkatcells) with a K_(D) of less than about 0.1 nM, 0.075 nM, 0.05 nM, 0.025nM, or 0.01 nM, e.g., about 0.06 nM, e.g., as measured by FACS analysis.

In some embodiments, the aforesaid antibody molecules bind to cynomolgusT cells with a K_(D) of less than about 1 nM, 0.75 nM, 0.5 nM, 0.25 nM,or 0.1 nM, e.g., about 0.4 nM, e.g., as measured by FACS analysis.

In some embodiments, the aforesaid antibody molecules bind to cells thatexpress cynomolgus PD-1 (e.g., cells transfected with cynomolgus PD-1)with a K_(D) of less than about 1 nM, 0.75 nM, 0.5 nM, 0.25 nM, or 0.01nM, e.g., about 0.6 nM, e.g., as measured by FACS analysis.

In certain embodiments, the aforesaid antibody molecules are notcross-reactive with mouse or rat PD-1. In other embodiments, theaforesaid antibodies are cross-reactive with rhesus PD-1. For example,the cross-reactivity can be measured by a Biacore method or a bindingassay using cells that expresses PD-1 (e.g., human PD-1-expressing300.19 cells). In other embodiments, the aforesaid antibody moleculesbind an extracellular Ig-like domain of PD-1.

In other embodiments, the aforesaid antibody molecules are capable ofreducing binding of PD-1 to PD-L1, PD-L2, or both, or a cell thatexpresses PD-L1, PD-L2, or both. In some embodiments, the aforesaidantibody molecules reduce (e.g., block) PD-L1 binding to a cell thatexpresses PD-1 (e.g., human PD-1-expressing 300.19 cells) with an IC50of less than about 1.5 nM, 1 nM, 0.8 nM, 0.6 nM, 0.4 nM, 0.2 nM, or 0.1nM, e.g., between about 0.79 nM and about 1.09 nM, e.g., about 0.94 nM,or about 0.78 nM or less, e.g., about 0.3 nM. In some embodiments, theaforesaid antibodies reduce (e.g., block) PD-L2 binding to a cell thatexpresses PD-1 (e.g., human PD-1-expressing 300.19 cells) with an IC50of less than about 2 nM, 1.5 nM, 1 nM, 0.5 nM, or 0.2 nM, e.g., betweenabout 1.05 nM and about 1.55 nM, or about 1.3 nM or less, e.g., about0.9 nM.

In other embodiments, the aforesaid antibody molecules are capable ofenhancing an antigen-specific T cell response.

In embodiments, the antibody molecule is a monospecific antibodymolecule or a bispecific antibody molecule. In embodiments, the antibodymolecule has a first binding specificity for PD-1 and a second bindingspecifity for TIM-3, LAG-3, CEACAM (e.g., CEACAM-1, CEACAM-3, and/orCEACAM-5), PD-L1 or PD-L2. In embodiments, the antibody moleculecomprises an antigen binding fragment of an antibody, e.g., a halfantibody or antigen binding fragment of a half antibody.

In some embodiments, the aforesaid antibody molecules increase theexpression of IL-2 from cells activated by Staphylococcal enterotoxin B(SEB) (e.g., at 25 μg/mL) by at least about 2, 3, 4, 5-fold, e.g., about2 to 3-fold, e.g., about 2 to 2.6-fold, e.g., about 2.3-fold, comparedto the expression of IL-2 when an isotype control (e.g., IgG4) is used,e.g., as measured in a SEB T cell activation assay or a human wholeblood ex vivo assay.

In some embodiments, the aforesaid antibody molecules increase theexpression of IFN-γ from T cells stimulated by anti-CD3 (e.g., at 0.1μg/mL) by at least about 2, 3, 4, 5-fold, e.g., about 1.2 to 3.4-fold,e.g., about 2.3-fold, compared to the expression of IFN-γ when anisotype control (e.g., IgG4) is used, e.g., as measured in an IFN-γactivity assay.

In some embodiments, the aforesaid antibody molecules increase theexpression of IFN-γ from T cells activated by SEB (e.g., at 3 pg/mL) byat least about 2, 3, 4, 5-fold, e.g., about 0.5 to 4.5-fold, e.g., about2.5-fold, compared to the expression of IFN-γ when an isotype control(e.g., IgG4) is used, e.g., as measured in an IFN-γ activity assay.

In some embodiments, the aforesaid antibody molecules increase theexpression of IFN-γ from T cells activated with an CMV peptide by atleast about 2, 3, 4, 5-fold, e.g., about 2 to 3.6-fold, e.g., about2.8-fold, compared to the expression of IFN-γ when an isotype control(e.g., IgG4) is used, e.g., as measured in an IFN-γ activity assay.

In some embodiments, the aforesaid antibody molecules increase theproliferation of CD8⁺ T cells activated with an CMV peptide by at leastabout 1, 2, 3, 4, 5-fold, e.g., about 1.5-fold, compared to theproliferation of CD8⁺ T cells when an isotype control (e.g., IgG4) isused, e.g., as measured by the percentage of CD8+ T cells that passedthrough at least n (e.g., n=2 or 4) cell divisions.

In certain embodiments, the aforesaid antibody molecules has a Cmaxbetween about 100 μg/mL and about 500 μg/mL, between about 150 μg/mL andabout 450 μg/mL, between about 250 μg/mL and about 350 μg/mL, or betweenabout 200 μg/mL and about 400 μg/mL, e.g., about 292.5 μg/mL, e.g., asmeasured in monkey.

In certain embodiments, the aforesaid antibody molecules has a T_(1/2)between about 250 hours and about 650 hours, between about 300 hours andabout 600 hours, between about 350 hours and about 550 hours, or betweenabout 400 hours and about 500 hours, e.g., about 465.5 hours, e.g., asmeasured in monkey.

In some embodiments, the aforesaid antibody molecules bind to PD-1 witha Kd slower than 5×10⁻⁴, 1×10⁻⁴, 5×10⁻⁵, or 1×10⁻⁵ s⁻¹, e.g., about2.13×10⁻⁴ s⁻¹, e.g., as measured by a Biacore method. In someembodiments, the aforesaid antibody molecules bind to PD-1 with a Kafaster than 1×10⁴, 5×10⁴, 1×10⁵, or 5×10⁵ M⁻¹s⁻¹, e.g., about 2.78×10⁵M⁻¹s⁻¹, e.g., as measured by a Biacore method.

In some embodiments, the aforesaid anti-PD-1 antibody molecules bind toone or more residues within the C strand, CC′ loop, C′ strand and FGloop of PD-1. The domain structure of PD-1 is described, e.g., in Chenget al., “Structure and Interactions of the Human Programmed Cell Death 1Receptor” J. Biol. Chem. 2013, 288:11771-11785. As described in Chenget. al., the C strand comprises residues F43-M50, the CC′ loop comprisesS51-N54, the C′ strand comprises residues Q55-F62, and the FG loopcomprises residues L1084114 (amino acid numbering according to Chang etal. supra). Accordingly, in some embodiments, an anti-PD-1 antibody asdescribed herein binds to at least one residue in one or more of theranges F43-M50, S51-N54, Q55-F62, and L1084114 of PD-1. In someembodiments, an anti-PD-1 antibody as described herein binds to at leastone residue in two, three, or all four of the ranges F43-M50, S51-N54,Q55-F62, and L1084114 of PD-1. In some embodiments, the anti-PD-1antibody binds to a residue in PD-1 that is also part of a binding sitefor one or both of PD-L1 and PD-L2.

In another aspect, the invention provides an isolated nucleic acidmolecule encoding any of the aforesaid antibody molecules, vectors andhost cells thereof.

An isolated nucleic acid encoding the antibody heavy chain variableregion or light chain variable region, or both, of any the aforesaidantibody molecules is also provided.

In one embodiment, the isolated nucleic acid encodes heavy chain CDRs1-3, wherein said nucleic acid comprises a nucleotide sequence of SEQ IDNO: 108-112, 223, 122-126, 133-137, or 144-146.

In another embodiment, the isolated nucleic acid encodes light chainCDRs 1-3, wherein said nucleic acid comprises a nucleotide sequence ofSEQ ID NO: 113-120, 127-132, or 138-143.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain variable domain, wherein saidnucleotide sequence is at least 85% identical to any of SEQ ID NO: 39,51, 83, 87, 90, 95, or 101.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain variable domain, wherein saidnucleotide sequence comprises any of SEQ ID NO: 39, 51, 83, 87, 90, 95,or 101.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain, wherein said nucleotidesequence is at least 85% identical to any of SEQ ID NO: 41, 53, 85, 89,92, 96, or 103.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a heavy chain, wherein said nucleotidesequence comprises any of SEQ ID NO: 41, 53, 85, 89, 92, 96, or 103.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain variable domain, wherein saidnucleotide sequence is at least 85% identical to any of SEQ ID NO: 45,49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105, or 107.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain variable domain, wherein saidnucleotide sequence comprises any of SEQ ID NO: 45, 49, 57, 61, 65, 69,73, 77, 81, 94, 98, 100, 105, or 107.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain, wherein said nucleotidesequence is at least 85% identical to any of SEQ ID NO: 45, 49, 57, 61,65, 69, 73, 77, 81, 94, 98, 100, 105 or 107.

In other embodiments, the aforesaid nucleic acid further comprises anucleotide sequence encoding a light chain, wherein said nucleotidesequence comprises any of SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81,94, 98, 100, 105 or 107.

In certain embodiments, one or more expression vectors and host cellscomprising the aforesaid nucleic acids are provided.

A method of producing an antibody molecule or fragment thereof,comprising culturing the host cell as described herein under conditionssuitable for gene expression is also provided.

Pharmaceutical Compositions and Kits

In another aspect, the present invention provides compositions, e.g.,pharmaceutically acceptable compositions, which include an antibodymolecule described herein, formulated together with a pharmaceuticallyacceptable carrier. As used herein, “pharmaceutically acceptablecarrier” includes any and all solvents, dispersion media, isotonic andabsorption delaying agents, and the like that are physiologicallycompatible. The carrier can be suitable for intravenous, intramuscular,subcutaneous, parenteral, rectal, spinal or epidermal administration(e.g. by injection or infusion).

The compositions of this invention may be in a variety of forms. Theseinclude, for example, liquid, semi-solid and solid dosage forms, such asliquid solutions (e.g., injectable and infusible solutions), dispersionsor suspensions, liposomes and suppositories. The preferred form dependson the intended mode of administration and therapeutic application.Typical preferred compositions are in the form of injectable orinfusible solutions. The preferred mode of administration is parenteral(e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). In apreferred embodiment, the antibody is administered by intravenousinfusion or injection. In another preferred embodiment, the antibody isadministered by intramuscular or subcutaneous injection.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, epidural and intrasternal injection andinfusion.

Therapeutic compositions typically should be sterile and stable underthe conditions of manufacture and storage. The composition can beformulated as a solution, microemulsion, dispersion, liposome, or otherordered structure suitable to high antibody concentration. Sterileinjectable solutions can be prepared by incorporating the activecompound (i.e., antibody or antibody portion) in the required amount inan appropriate solvent with one or a combination of ingredientsenumerated above, as required, followed by filtered sterilization.Generally, dispersions are prepared by incorporating the active compoundinto a sterile vehicle that contains a basic dispersion medium and therequired other ingredients from those enumerated above. In the case ofsterile powders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and freeze-dryingthat yields a powder of the active ingredient plus any additionaldesired ingredient from a previously sterile-filtered solution thereof.The proper fluidity of a solution can be maintained, for example, by theuse of a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.Prolonged absorption of injectable compositions can be brought about byincluding in the composition an agent that delays absorption, forexample, monostearate salts and gelatin.

The antibody molecules can be administered by a variety of methods knownin the art, although for many therapeutic applications, the preferredroute/mode of administration is intravenous injection or infusion. Forexample, the antibody molecules can be administered by intravenousinfusion at a rate of more than 20 mg/min, e.g., 20-40 mg/min, andtypically greater than or equal to 40 mg/min to reach a dose of about 35to 440 mg/m², typically about 70 to 310 mg/m², and more typically, about110 to 130 mg/m². In embodiments, the antibody molecules can beadministered by intravenous infusion at a rate of less than 10 mg/min;preferably less than or equal to 5 mg/min to reach a dose of about 1 to100 mg/m², preferably about 5 to 50 mg/m², about 7 to 25 mg/m² and morepreferably, about 10 mg/m². As will be appreciated by the skilledartisan, the route and/or mode of administration will vary dependingupon the desired results. In certain embodiments, the active compoundmay be prepared with a carrier that will protect the compound againstrapid release, such as a controlled release formulation, includingimplants, transdermal patches, and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylenevinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Many methods for the preparationof such formulations are patented or generally known to those skilled inthe art. See, e.g., Sustained and Controlled Release Drug DeliverySystems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, an antibody molecule can be orally administered,for example, with an inert diluent or an assimilable edible carrier. Thecompound (and other ingredients, if desired) may also be enclosed in ahard or soft shell gelatin capsule, compressed into tablets, orincorporated directly into the subject's diet. For oral therapeuticadministration, the compounds may be incorporated with excipients andused in the form of ingestible tablets, buccal tablets, troches,capsules, elixirs, suspensions, syrups, wafers, and the like. Toadminister a compound of the invention by other than parenteraladministration, it may be necessary to coat the compound with, orco-administer the compound with, a material to prevent its inactivation.Therapeutic compositions can also be administered with medical devicesknown in the art.

Dosage regimens are adjusted to provide the optimum desired response(e.g., a therapeutic response). For example, a single bolus may beadministered, several divided doses may be administered over time or thedose may be proportionally reduced or increased as indicated by theexigencies of the therapeutic situation. It is especially advantageousto formulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suited as unitary dosages for thesubjects to be treated; each unit contains a predetermined quantity ofactive compound calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical carrier. The specificationfor the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the active compound andthe particular therapeutic effect to be achieved, and (b) thelimitations inherent in the art of compounding such an active compoundfor the treatment of sensitivity in individuals.

An exemplary, non-limiting range for a therapeutically orprophylactically effective amount of an antibody molecule is 0.1-30mg/kg, more preferably 1-25 mg/kg. Dosages and therapeutic regimens ofthe anti-PD-1 antibody molecule can be determined by a skilled artisan.In certain embodiments, the anti-PD-1 antibody molecule is administeredby injection (e.g., subcutaneously or intravenously) at a dose of about1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10to 20 mg/kg, about 1 to 5 mg/kg, 1 to 10 mg/kg, 5 to 15 mg/kg, 10 to 20mg/kg, 15 to 25 mg/kg, or about 3 mg/kg. The dosing schedule can varyfrom e.g., once a week to once every 2, 3, or 4 weeks. In oneembodiment, the anti-PD-1 antibody molecule is administered at a dosefrom about 10 to 20 mg/kg every other week. The antibody molecule can beadministered by intravenous infusion at a rate of more than 20 mg/min,e.g., 20-40 mg/min, and typically greater than or equal to 40 mg/min toreach a dose of about 35 to 440 mg/m², typically about 70 to 310 mg/m²,and more typically, about 110 to 130 mg/m². In embodiments, the infusionrate of about 110 to 130 mg/m² achieves a level of about 3 mg/kg. Inother embodiments, the antibody molecule can be administered byintravenous infusion at a rate of less than 10 mg/min, e.g., less thanor equal to 5 mg/min to reach a dose of about 1 to 100 mg/m², e.g.,about 5 to 50 mg/m², about 7 to 25 mg/m², or, about 10 mg/m². In someembodiments, the antibody is infused over a period of about 30 min. Itis to be noted that dosage values may vary with the type and severity ofthe condition to be alleviated. It is to be further understood that forany particular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions, and that dosage ranges set forth herein are exemplary onlyand are not intended to limit the scope or practice of the claimedcomposition.

The pharmaceutical compositions of the invention may include a“therapeutically effective amount” or a “prophylactically effectiveamount” of an antibody or antibody portion of the invention. A“therapeutically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredtherapeutic result. A therapeutically effective amount of the modifiedantibody or antibody fragment may vary according to factors such as thedisease state, age, sex, and weight of the individual, and the abilityof the antibody or antibody portion to elicit a desired response in theindividual. A therapeutically effective amount is also one in which anytoxic or detrimental effects of the modified antibody or antibodyfragment is outweighed by the therapeutically beneficial effects. A“therapeutically effective dosage” preferably inhibits a measurableparameter, e.g., tumor growth rate by at least about 20%, morepreferably by at least about 40%, even more preferably by at least about60%, and still more preferably by at least about 80% relative tountreated subjects. The ability of a compound to inhibit a measurableparameter, e.g., cancer, can be evaluated in an animal model systempredictive of efficacy in human tumors. Alternatively, this property ofa composition can be evaluated by examining the ability of the compoundto inhibit, such inhibition in vitro by assays known to the skilledpractitioner.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, since a prophylactic dose is used insubjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

Also within the scope of the invention is a kit comprising an antibodymolecule described herein. The kit can include one or more otherelements including: instructions for use; other reagents, e.g., a label,a therapeutic agent, or an agent useful for chelating, or otherwisecoupling, an antibody to a label or therapeutic agent, or aradioprotective composition; devices or other materials for preparingthe antibody for administration; pharmaceutically acceptable carriers;and devices or other materials for administration to a subject.

Uses of Anti-PD-1 Antibody Molecules

The anti-PD-1 antibody molecules disclosed herein have in vitro and invivo diagnostic, as well as therapeutic and prophylactic utilities. Forexample, these molecules can be administered to cells in culture, invitro or ex vivo, or to a subject, e.g., a human subject, to treat,prevent, and/or diagnose a variety of disorders, such as cancers andinfectious disorders.

Accordingly, in one aspect, the invention provides a method of modifyingan immune response in a subject comprising administering to the subjectthe antibody molecule described herein, such that the immune response inthe subject is modified. In one embodiment, the immune response isenhanced, stimulated or up-regulated. In one embodiment, the antibodymolecules enhance an immune response in a subject by blockade of PD-1.

As used herein, the term “subject” is intended to include human andnon-human animals. In one embodiment, the subject is a human subject,e.g., a human patient having a disorder or condition characterized byabnormal PD-1 functioning. The term “non-human animals” includes mammalsand non-mammals, such as non-human primates. In one embodiment, thesubject is a human. In one embodiment, the subject is a human patient inneed of enhancement of an immune response. In one embodiment, thesubject is immunocompromised, e.g., the subject is undergoing, or hasundergone a chemotherapeutic or radiation therapy. Alternatively, or incombination, the subject is, or is at risk of being, immunocompromisedas a result of an infection. The methods and compositions describedherein are suitable for treating human patients having a disorder thatcan be treated by augmenting the T-cell mediated immune response. Forexample, the methods and compositions described herein can enhance anumber of immune activities. In one embodiment, the subject hasincreased number or activity of tumour-infiltrating T lymphocytes(TILs). In another embodiment, the subject has increased expression oractivity of interferon-gamma (IFN-γ). In yet another embodiment, thesubject has decreased PD-L1 expression or activity.

Therapeutic Uses Cancer

Blockade of PD-1 can enhance an immune response to cancerous cells in asubject. The ligand for PD-1, PD-L1, is not expressed in normal humancells, but is abundant in a variety of human cancers (Dong et al. (2002)Nat Med 8:787-9). The interaction between PD-1 and PD-L1 can result in adecrease in tumor infiltrating lymphocytes, a decrease in T-cellreceptor mediated proliferation, and/or immune evasion by the cancerouscells (Dong et al. (2003) J Mol Med 81:281-7; Blank et al. (2005) CancerImmunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res.10:5094-100). Immune suppression can be reversed by inhibiting the localinteraction of PD-1 to PD-L1; the effect is additive when theinteraction of PD-1 to PD-L2 is blocked as well (Iwai et al. (2002) PNAS99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). Thus,inhibition of PD-1 can result in augmenting an immune response.

In one aspect, the invention relates to treatment of a subject in vivousing an anti-PD-1 antibody molecule such that growth of canceroustumors is inhibited or reduced. An anti-PD-1 antibody may be used aloneto inhibit the growth of cancerous tumors. Alternatively, an anti-PD-1antibody may be used in combination with one or more of: a standard ofcare treatment (e.g., for cancers or infectious disorders), anotherantibody or antigen-binding fragment thereof, an immunomodulator (e.g.,an activator of a costimulatory molecule or an inhibitor of aninhibitory molecule); a vaccine, e.g., a therapeutic cancer vaccine; orother forms of cellular immunotherapy, as described below.

Accordingly, in one embodiment, the invention provides a method ofinhibiting growth of tumor cells in a subject, comprising administeringto the subject a therapeutically effective amount of an anti-PD-1antibody molecule described herein.

In one embodiment, the methods are suitable for the treatment of cancerin vivo. To achieve antigen-specific enhancement of immunity, theanti-PD-1 antibody molecule can be administered together with an antigenof interest. When antibodies to PD-1 are administered in combinationwith one or more agents, the combination can be administered in eitherorder or simultaneously.

Types of Cancer; Theranostic Methods

In another aspect, a method of treating a subject, e.g., reducing orameliorating, a hyperproliferative condition or disorder (e.g., acancer), e.g., solid tumor, a hematological cancer, soft tissue tumor,or a metastatic lesion, in a subject is provided. The method includesadministering to the subject one or more anti-PD-1 antibody moleculesdescribed herein, alone or in combination with other agents ortherapeutic modalities.

As used herein, the term “cancer” is meant to include all types ofcancerous growths or oncogenic processes, metastatic tissues ormalignantly transformed cells, tissues, or organs, irrespective ofhistopathologic type or stage of invasiveness. Examples of cancerousdisorders include, but are not limited to, solid tumors, hematologicalcancers, soft tissue tumors, and metastatic lesions. Examples of solidtumors include malignancies, e.g., sarcomas, and carcinomas (includingadenocarcinomas and squamous cell carcinomas), of the various organsystems, such as those affecting liver, lung, breast, lymphoid,gastrointestinal (e.g., colon), genitourinary tract (e.g., renal,urothelial cells), prostate and pharynx. Adenocarcinomas includemalignancies such as most colon cancers, rectal cancer, renal-cellcarcinoma, liver cancer, non-small cell carcinoma of the lung, cancer ofthe small intestine and cancer of the esophagus. Squamous cellcarcinomas include malignancies, e.g., in the lung, esophagus, skin,head and neck region, oral cavity, anus, and cervix. In one embodiment,the cancer is a melanoma, e.g., an advanced stage melanoma. Metastaticlesions of the aforementioned cancers can also be treated or preventedusing the methods and compositions of the invention.

Exemplary cancers whose growth can be inhibited using the antibodiesmolecules disclosed herein include cancers typically responsive toimmunotherapy. Non-limiting examples of preferred cancers for treatmentinclude melanoma (e.g., metastatic malignant melanoma), renal cancer(e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractoryprostate adenocarcinoma), breast cancer, colon cancer and lung cancer(e.g., non-small cell lung cancer). Additionally, refractory orrecurrent malignancies can be treated using the antibody moleculesdescribed herein.

Examples of other cancers that can be treated include bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, anal cancer, gastro-esophageal, stomach cancer, testicularcancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma ofthe endometrium, carcinoma of the cervix, carcinoma of the vagina,carcinoma of the vulva, Merkel cell cancer, Hodgkin lymphoma,non-Hodgkin lymphoma, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, chronic oracute leukemias including acute myeloid leukemia, chronic myeloidleukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia,solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder,multiple myeloma, myelodisplastic syndromes, cancer of the kidney orureter, carcinoma of the renal pelvis, neoplasm of the central nervoussystem (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axistumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma,epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos(e.g., mesothelioma), and combinations of said cancers.

Treatment of metastatic cancers, e.g., metastatic cancers that expressPD-L1 (Iwai et al. (2005) Int. Immunol. 17:133-144) can be effectedusing the antibody molecules described herein. In one embodiment, thecancer expresses an elevated level of PD-L1, IFNγ and/or CD8.

While not wishing to be bound by theory, in some embodiments, a patientis more likely to respond to treatment with an immunomodulator(optionally in combination with one or more agents as described herein)if the patient has a cancer that highly expresses PD-L1, and/or thecancer is infiltrated by anti-tumor immune cells, e.g., TILs. Theanti-tumor immunce cells may be positive for CD8, PD-L1, and/or IFN-γ;thus levels of CD8, PD-L1, and/or IFN-γ can serve as a readout forlevels of TILs in the microenvironment. In certain embodiments, thecancer microenvironment is referred to as triple-positive forPD-L1/CD8/IFN-γ.

Accordingly, in certain aspects, this application provides methods ofdetermining whether a tumor sample is positive for one or more of PD-L1,CD8, and IFN-γ, and if the tumor sample is positive for one or more,e.g., two, or all three, of the markers, then administering to thepatient a therapeutically effective amount of an anti-PD-1 antibodymolecule, optionally in combination with one or more otherimmunnomodulators or anti-cancer agents.

In the following indications, a large fraction of patients aretriple-positive for PD-L1/CD8/IFN-γ: Lung cancer (squamous); lung cancer(adenocarcinoma); head and neck cancer; stomach cancer; NSCLC; HNSCC;gastric cancers (e.g., MSIhi and/or EBV+); CRC (e.g., MSIhi);nasopharyngeal cancer (NPC); cervical cancer (e.g., squamous); thyroidcancer e.g., papillary thyroid; melanoma; TN breast cancer; and DLBCL(Diffuse Large B-Cell Lymphoma). In breast cancer generally and in coloncancer generally, a moderate fraction of patients is triple-positive forPD-L1/CD8/IFN-γ. In the following indications, a small fraction ofpatients are triple-positive for PD-L1/CD8/IFN-γ: ER+ breast cancer, andpancreatic cancer. These findings are discussed further in Example 4.Regardless of whether a large or small fraction of patients istriple-positive for these markers, screening the patients for thesemarkers allows one to identify a fraction of patients that has anespecially high likelihood of responding favorably to therapy with aPD-1 antibody (e.g., a blocking PD-1 antibody), optionally incombination with one or more other immunomodulators (e.g., an anti-TIM-3antibody molecule, an anti-LAG-3 antibody molecule, or an anti-PD-L1antibody molecule) and/or anti-cancer agents, e.g., those listed inTable 7 and disclosed in the publications listed in Table 7.

In some embodiments, the cancer sample is classified as triple-positivefor PD-L1/CD8/IFN-γ. This measurement can roughly be broken down intotwo thresholds: whether an individual cell is classified as positive,and whether the sample as a whole is classified as positive. First, onecan measure, within an individual cell, the level of PD-L1, CD8, and/orIFN-γ. In some embodiments, a cell that is positive for one or more ofthese markers is a cell that has a higher level of the marker comparedto a control cell or a reference value. For example, in someembodiments, a high level of PD-L1 in a given cell is a level higherthan the level of PD-L1 in a corresponding non-cancerous tissue in thepatient. As another example, in some embodiments, a high level of CD8 orIFN-γ in a given cell is a level of that protein typically seen in aTIL. Second, one can also measure the percentage of cells in the samplethat are positive for PD-L1, CD8, and/or IFN-γ. (It is not necessary fora single cell to express all three markers.) In some embodiments, atriple positive sample is one that has a high percentage of cells, e.g.,higher than a reference value or higher than a control sample, that arepositive for these markers.

In other embodiments, one can measure the levels of PD-L1, CD8, and/orIFN-γ overall in the sample. In this case, a high level of CD8 or IFN-γin the sample can be the level of that protein typically seen in a tumorinfiltrated with TIL. Similarly, a high level of PD-L1 can be the levelof that protein typically seen in a tumor sample, e.g., a tumormicroenvironment.

The identification of subsets of patients that are triple-positive forPD-L1/CD8/IFN-γ, as shown in Example 4 herein, reveals certainsub-populations of patients that are likely to be responsive to PD-1antibody therapy. For instance, many IM-TN (immunomodulatory, triplenegative) breast cancer patients are triple-positive forPD-L1/CD8/IFN-γ. IM-TN breast cancer is described in, e.g., Brian D.Lehmann et al., “Identification of human triple-negative breast cancersubtypes and preclinical models for selection of targeted therapies”, JClin Invest. Jul. 1, 2011; 121(7): 2750-2767. Triple-negative breastcancers are those that do not express estrogen receptor (ER),progesterone receptor (PR) and Her2/neu. These cancers are difficult totreat because they are typically not responsive to agents that targetER, PR, and Her2/neu. Triple-negative breast cancers can be furthersubdivided into different classes, one of which is immunomodulatory. Asdescribed in Lehmann et al., IM-TN breast cancer is enriched for factorsinvolved in immune cell processes, for example, one or more of immunecell signaling (e.g., TH1/TH2 pathway, NK cell pathway, B cell receptorsignaling pathway, DC pathway, and T cell receptor signaling), cytokinesignaling (e.g., cytokine pathway, IL-12 pathway, and IL-7 pathway),antigen processing and presentation, signaling through core immunesignal transduction pathways (e.g., NFKB, TNF, and JAK/STAT signaling),genes involved in T-cell function, immune transcription, interferon(IFN) response and antigen processing. Accordingly, in some embodiments,the cancer treated is a cancer that is, or is determined to be, positivefor one or more marker of IM-TN breast cancer, e.g., a factor thatpromotes one or more of immune cell signaling (e.g., TH1/TH2 pathway, NKcell pathway, B cell receptor signaling pathway, DC pathway, and T cellreceptor signaling), cytokine signaling (e.g., cytokine pathway, IL-12pathway, and IL-7 pathway), antigen processing and presentation,signaling through core immune signal transduction pathways (e.g., NFKB,TNF, and JAK/STAT signaling), genes involved in T-cell function, immunetranscription, interferon (IFN) response and antigen processing.

As another example, it is shown herein that a subset of colon cancerpatients having high MSI (microsatellite instability) is alsotriple-positive for PD-L1/CD8/IFN-γ. Accordingly, in some embodiments, aPD-1 antibody, e.g., a PD-1 antibody as described herein, (optionally incombination with one or more immunomodulators such as a LAG-3 antibody,TIM-3 antibody, or PD-L1 antibody, and one or more anti-cancer agents,e.g., an anti-cancer agent described in Table 7 or in a publication inTable 7) is administered to a patient who has, or who is identified ashaving, colon cancer with high MSI, thereby treating the cancer. In someembodiments, a cell with high MSI is a cell having MSI at a level higherthan a reference value or a control cell, e.g., a non-cancerous cell ofthe same tissue type as the cancer.

As another example, it is shown herein that a subset of gastric cancerpatients having high MSI, and/or which is EBV+, is also triple-positivefor PD-L1/CD8/IFN-γ. Accordingly, in some embodiments, a PD-1 antibody,e.g., a PD-1 antibody as described herein, (optionally in combinationwith one or more immunomodulators such as a LAG-3 antibody, TIM-3antibody, or PD-L1 antibody, and one or more anti-cancer agents, e.g.,an anti-cancer agent described in Table 7 or in a publication in Table7) is administered to a patient who has, or who is identified as having,gastric cancer with high MSI and/or EBV+, thereby treating the cancer.In some embodiments, a cell with high MSI is a cell having MSI at alevel higher than a reference value or a control cell, e.g., anon-cancerous cell of the same tissue type as the cancer.

Additionally disclosed herein are methods of assaying a cancer forPD-L1, and then treating the cancer with a PD-1 antibody. As describedin Example 5 herein, a cancer sample can be assayed for PD-L1 proteinlevels or mRNA levels. A sample having levels of PD-L1 (protein or mRNA)higher than a reference value or a control cell (e.g., a non-cancerouscell) can be classified as PD-L1 positive. Accordingly, in someembodiments, a PD-1 antibody, e.g., a PD-1 antibody as described herein,(optionally in combination with one or more anti-cancer agents) isadministered to a patient who has, or who is identified as having, acancer that is PD-L1 positive. The cancer may be, e.g., non-small celllung (NSCLC) adenocarcinoma (ACA), NSCLC squamous cell carcinoma (SCC),or hepatocellular carcinoma (HCC).

In some embodiments, the methods herein involve using a PD-1 antibody,e.g., a PD-1 antibody as described herein, e.g., as a monotherapy, fortreating a cancer that is (or is identified as being) positive forPD-L1. In some embodiments, the cancer is colorectal cancer (e.g.,MSI-high), gastric cancer (e.g., MSI-high and/or EBV+), NPC, cervicalcancer, breast cancer (e.g., TN breast cancer), and ovarian cancer. Insome embodiments, the cancer is NSCLC, melanoma, or HNSCC. In someembodiments, the PD-1 antibody is administered at a dose of, e.g., 1, 3,10, or 20 mg/kg.

Based on, e.g, Example 4 herein, it was found that certain gastriccancers that are triple-positive for PD-L1/CD8/IFN-γ are also positivefor PIK3CA. Accordingly, in some embodiments, a cancer can be treatedwith an anti-PD-1 antibody molecule (optionally in combination with oneor more immunomodulators, e.g., an anti-LAG-3 antibody molecule, ananti-TIM-3 antibody molecule, or an anti-PD-L1 antibody molecule) and anagent that inhibits PIK3CA. Exemplary agents in this category aredescribed in Stein R C (September 2001). “Prospects for phosphoinositide3-kinase inhibition as a cancer treatment”. Endocrine-related Cancer 8(3): 237-48 and Marone R, Cmiljanovic V, Giese B, Wymann M P (January2008). “Targeting phosphoinositide 3-kinase: moving towards therapy”.Biochimica et Biophysica Acta 1784 (1): 159-85.

Based on, e.g, Example 4 herein, CRC, e.g., a patient that has (or isidentified as having) MSI-high CRC may be treated with a PD-1 antibody,optionally in combination with a therapeutic that targets one or more ofLAG-3, RNF43, and BRAF. For instance, these cancers may be treated witha PD-1 antibody, optionally in combination with one or more therapeuticsthat target one or more of LAG-3, PD-1, RNF43, and BRAF. In embodiments,the one or more therapeutics include an immunomodulators such as ananti-LAG-3 antibody molecule, and an anti-cancer agent described inTable 7 or a publication listed in Table 7. LAG-3 inhibitors, e.g.,antibodies, are described herein. RNF43 can be inhibited, e.g., with anantibody, small molecule (e.g.,2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28)), siRNA, or a Rspo ligand or derivative thereof. BRAFinhibitors (e.g., vemurafenib or dabrafenib) are described herein.

Based on, e.g, Example 4 herein, a patient that has (or is identified ashaving) a squamous cell lung cancer may be treated with a PD-1 antibodymolecule in combination with a therapeutic that targets LAG-3, e.g., aLAG-3 antibody molecule, and optionally with one or more anti-canceragents, e.g., an anti-cancer agent described in Table 7 or in apublication in Table 7.

In some embodiments, a subject that has (or is identified as having) asquamous cell lung cancer may be treated with a PD-1 antibody,optionally in combination with a therapeutic that targets TIM-3, e.g., aTIM-3 antibody. TIM-3 inhibitors, e.g., antibodies, are describedherein.

Based on, e.g, Example 4 herein, a patient that has (or is identified ashaving) a thyroid cancer may be treated with a PD-1 antibody molecule,optionally in combination with a therapeutic that targets BRAF, andoptionally in combination with one or more immunomodulators, e.g., ananti-LAG-3 antibody molecule, an anti-TIM-3 antibody molecule, and ananti-PD-L1 antibody molecule. BRAF inhibitors (e.g., vemurafenib ordabrafenib) are described herein, e.g., in Table 7 and the publicationslisted in Table 7.

In some embodiments, the therapies here can be used to treat a patientthat has (or is identified as having) a cancer associated with aninfection, e.g., a viral or bacterial infection. Exemplary cancersinclude cervical cancer, anal cancer, HPV-associated head and necksquamous cell cancer, HPV-associated esophageal papillomas,HHV6-associated lymphomas, EBV-associated lymphomas (including Burkittlymphoma), Gastric MALT lymphoma, other infection-associated MALTlymphomas, HCC, and Kaposi's sarcoma.

In other embodiments, the cancer is a hematological malignancy or cancerincluding but is not limited to a leukemia or a lymphoma. For example,the anti-PD-1 antibody molecule can be used to treat cancers andmalignancies including, but not limited to, e.g., acute leukemiasincluding but not limited to, e.g., B-cell acute lymphoid leukemia(“BALL”), T-cell acute lymphoid leukemia (“TALL”), acute lymphoidleukemia (ALL); one or more chronic leukemias including but not limitedto, e.g., chronic myelogenous leukemia (CML), chronic lymphocyticleukemia (CLL); additional hematologic cancers or hematologic conditionsincluding, but not limited to, e.g., B cell prolymphocytic leukemia,blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma,diffuse large B cell lymphoma, Follicular lymphoma, Hairy cell leukemia,small cell- or a large cell-follicular lymphoma, malignantlymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma,Marginal zone lymphoma, multiple myeloma, myelodysplasia andmyelodysplastic syndrome, non-Hodgkin lymphoma, plasmablastic lymphoma,plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, and“preleukemia” which are a diverse collection of hematological conditionsunited by ineffective production (or dysplasia) of myeloid blood cells,and the like.

In one embodiment, the cancer is chosen from a lung cancer (e.g., anon-small cell lung cancer (NSCLC) (e.g., a NSCLC with squamous and/ornon-squamous histology, or a NSCLC adenocarcinoma)), a melanoma (e.g.,an advanced melanoma), a renal cancer (e.g., a renal cell carcinoma,e.g., clear cell renal cell carcinoma), a liver cancer, a myeloma (e.g.,a multiple myeloma), a prostate cancer, a breast cancer (e.g., a breastcancer that does not express one, two or all of estrogen receptor,progesterone receptor, or Her2/neu, e.g., a triple negative breastcancer), a colorectal cancer, a pancreatic cancer, a head and neckcancer (e.g., head and neck squamous cell carcinoma (HNSCC), analcancer, gastro-esophageal cancer, thyroid cancer, cervical cancer, alymphoproliferative disease (e.g., a post-transplant lymphoproliferativedisease) or a hematological cancer, T-cell lymphoma, a non-Hogdkin'slymphoma, or a leukemia (e.g., a myeloid leukemia).

In another embodiment, the cancer is chosen form a carcinoma (e.g.,advanced or metastatic carcinoma), melanoma or a lung carcinoma, e.g., anon-small cell lung carcinoma.

In one embodiment, the cancer is a lung cancer, e.g., a non-small celllung cancer.

In another embodiment, the cancer is a hepatocarcinoma, e.g., anadvanced hepatocarcinoma, with or without a viral infection, e.g., achronic viral hepatitis.

In another embodiment, the cancer is a prostate cancer, e.g., anadvanced prostate cancer.

In yet another embodiment, the cancer is a myeloma, e.g., multiplemyeloma.

In yet another embodiment, the cancer is a renal cancer, e.g., a renalcell carcinoma (RCC) (e.g., a metastatic RCC or clear cell renal cellcarcinoma).

In one embodiment, the cancer is a melanoma, e.g., an advanced melanoma.In one embodiment, the cancer is an advanced or unresectable melanomathat does not respond to other therapies. In other embodiments, thecancer is a melanoma with a BRAF mutation (e.g., a BRAF V600 mutation).In yet other embodiments, the anti-PD-1 antibody molecule isadministered after treatment with an anti-CTLA-4 antibody (e.g.,ipilimumab) with or without a BRAF inhibitor (e.g., vemurafenib ordabrafenib).

Methods and compositions disclosed herein are useful for treatingmetastatic lesions associated with the aforementioned cancers.

Combination of Anti-PD-1 Antibodies with Cancer Vaccines

Antibody molecules to PD-1 can be combined with an immunogenic agent,such as cancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines (He et al.(2004) J. Immunol. 173:4919-28). Non-limiting examples of tumor vaccinesthat can be used include peptides of melanoma antigens, such as peptidesof gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, tumor cellstransfected to express the cytokine GM-CSF, DNA-based vaccines,RNA-based vaccines, and viral transduction-based vaccines. The cancervaccine may be prophylactic or therapeutic.

PD-1 blockade can be combined with a vaccination protocol. Manyexperimental strategies for vaccination against tumors have been devised(see Rosenberg, S., 2000, Development of Cancer Vaccines, ASCOEducational Book Spring: 60-62; Logothetis, C., 2000, ASCO EducationalBook Spring: 300-302; Khayat, D. 2000, ASCO Educational Book Spring:414-428; Foon, K. 2000, ASCO Educational Book Spring: 730-738; see alsoRestifo, N. and Sznol, M., Cancer Vaccines, Ch. 61, pp. 3023-3043 inDeVita, V. et al. (eds.), 1997, Cancer: Principles and Practice ofOncology. Fifth Edition). In one of these strategies, a vaccine isprepared using autologous or allogeneic tumor cells. These cellularvaccines have been shown to be most effective when the tumor cells aretransduced to express GM-CSF. GM-CSF has been shown to be a potentactivator of antigen presentation for tumor vaccination (Dranoff et al.(1993) Proc. Natl. Acad. Sci. U.S.A. 90: 3539-43).

PD-1 blockade can be used in conjunction with a collection ofrecombinant proteins and/or peptides expressed in a tumor in order togenerate an immune response to these proteins. These proteins arenormally viewed by the immune system as self antigens and are thereforetolerant to them. The tumor antigen may also include the proteintelomerase, which is required for the synthesis of telomeres ofchromosomes and which is expressed in more than 85% of human cancers andin only a limited number of somatic tissues (Kim, N et al. (1994)Science 266: 2011-2013). (These somatic tissues may be protected fromimmune attack by various means). Tumor antigen may also be“neo-antigens” expressed in cancer cells because of somatic mutationsthat alter protein sequence or create fusion proteins between twounrelated sequences (ie. bcr-abl in the Philadelphia chromosome), oridiotype from B cell tumors.

Other tumor vaccines may include the proteins from viruses implicated inhuman cancers such a Human Papilloma Viruses (HPV), Hepatitis Viruses(HBV and HCV), Kaposi's Herpes Sarcoma Virus (KHSV), and Epstein-Barrvirus (EBV). Another form of tumor specific antigen which may be used inconjunction with PD-1 blockade is purified heat shock proteins (HSP)isolated from the tumor tissue itself. These heat shock proteins containfragments of proteins from the tumor cells and these HSPs are highlyefficient at delivery to antigen presenting cells for eliciting tumorimmunity (Suot, R & Srivastava, P (1995) Science 269:1585-1588; Tamura,Y. et al. (1997) Science 278:117-120).

Dendritic cells (DC) are potent antigen presenting cells that can beused to prime antigen-specific responses. DC's can be produced ex vivoand loaded with various protein and peptide antigens as well as tumorcell extracts (Nestle, F. et al. (1998) Nature Medicine 4: 328-332). DCsmay also be transduced by genetic means to express these tumor antigensas well. DCs have also been fused directly to tumor cells for thepurposes of immunization (Kugler, A. et al. (2000) Nature Medicine6:332-336). As a method of vaccination, DC immunization may beeffectively combined with PD-1 blockade to activate more potentanti-tumor responses.

In embodiments, the combination further includes an inhibitor oractivator of an immune checkpoint modulator (e.g., a LAG-3 inhibitor(e.g., an anti-LAG-3 antibody molecule), a PD-L1 inhibitor (e.g., ananti-PD-L1 antibody molecule), a TIM-3 modulator (e.g., a TIM-3activator or inhibitor, e.g., an anti-TIM-3 antibody molecule), or aCTLA-4 inhibitor (e.g., an anti-CTLA-4 antibody), or any combinationthereof.

PD-1 blockade may also be combined with a standard cancer treatment.PD-1 blockade may be effectively combined with chemotherapeutic regimes.In these instances, it may be possible to reduce the dose ofchemotherapeutic reagent administered (Mokyr, M. et al. (1998) CancerResearch 58: 5301-5304). In certain embodiments, the methods andcompositions described herein are administered in combination with oneor more of other antibody molecules, chemotherapy, other anti-cancertherapy (e.g., targeted anti-cancer therapies, or oncolytic drugs),cytotoxic agents, immune-based therapies (e.g., cytokines), surgicaland/or radiation procedures. Exemplary cytotoxic agents that can beadministered in combination with include antimicrotubule agents,topoisomerase inhibitors, anti-metabolites, mitotic inhibitors,alkylating agents, anthracyclines, vinca alkaloids, intercalatingagents, agents capable of interfering with a signal transductionpathway, agents that promote apoptosis, proteosome inhibitors, andradiation (e.g., local or whole body irradiation).

Alternatively, or in combination with the aforesaid combinations, themethods and compositions described herein can be administered incombination with one or more of: an immunomodulator (e.g., an activatorof a costimulatory molecule or an inhibitor of an inhibitory molecule);a vaccine, e.g., a therapeutic cancer vaccine; or other forms ofcellular immunotherapy.

Exemplary non-limiting combinations and uses of the anti-PD-1 antibodymolecules include the following.

In certain embodiments, the anti-PD-1 antibody molecule is administeredin combination with a modulator of a costimulatory molecule or aninhibitory molecule, e.g., a co-inhibitory ligand or receptor.

In one embodiment, the anti-PD-1 antibody molecule is administered incombination with a modulator, e.g., agonist, of a costimulatorymolecule. In one embodiment, the agonist of the costimulatory moleculeis chosen from an agonist (e.g., an agonistic antibody orantigen-binding fragment thereof, or soluble fusion) of OX40, CD2, CD27,CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR,CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3or CD83 ligand.

In another embodiment, the anti-PD-1 antibody molecule is used incombination with a costimulatory molecule, e.g., an agonist associatedwith a positive signal that includes a costimulatory domain of CD28,CD27, ICOS and GITR.

Exemplary GITR agonists include, e.g., GITR fusion proteins andanti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as, aGITR fusion protein described in U.S. Pat. No. 6,111,090, EuropeanPatent No.: 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO2010/003118 and 2011/090754, or an anti-GITR antibody described, e.g.,in U.S. Pat. No. 7,025,962, European Patent No.: 1947183B1, U.S. Pat.No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886,European Patent No.: EP 1866339, PCT Publication No.: WO 2011/028683,PCT Publication No.: WO 2013/039954, PCT Publication No.: WO2005/007190,PCT Publication No.: WO 2007/133822, PCT Publication No.: WO2005/055808,PCT Publication No.: WO 99/40196, PCT Publication No.: WO 2001/03720,PCT Publication No.: WO99/20758, PCT Publication No.: WO2006/083289, PCTPublication No.: WO 2005/115451, U.S. Pat. No. 7,618,632, and PCTPublication No.: WO 2011/051726.

In one embodiment, the anti-PD-1 antibody molecule is administered incombination with an inhibitor of an inhibitory molecule of an immunecheckpoint molecule. It will be understood by those of ordinary skill inthe art, that the term “immune checkpoints” means a group of moleculeson the cell surface of CD4 and CD8 T cells. These molecules caneffectively serve as “brakes” to down-modulate or inhibit an anti-tumorimmune response. Immune checkpoint molecules include, but are notlimited to, Programmed Death 1 (PD-1), Cytotoxic T-Lymphocyte Antigen 4(CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, LAG-3 and TIM-3, whichdirectly inhibit immune cells. Immunotherapeutic agents which can act asimmune checkpoint inhibitors useful in the methods of the presentinvention, include, but are not limited to, inhibitors of PD-L1, PD-L2,CTLA4, TIM-3, LAG-3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, CEACAM(e.g., CEACAM-1 and/or CEACAM-5), and/or TGFR beta. Inhibition of aninhibitory molecule can be performed by inhibition at the DNA, RNA orprotein level. In embodiments, an inhibitory nucleic acid (e.g., adsRNA, siRNA or shRNA), can be used to inhibit expression of aninhibitory molecule. In other embodiments, the inhibitor of aninhibitory signal is, a polypeptide e.g., a soluble ligand, or anantibody or antigen-binding fragment thereof, that binds to theinhibitory molecule.

In one embodiment, the inhibitor is a soluble ligand (e.g., a CTLA-4-Igor a TIM-3-Ig), or an antibody or antibody fragment that binds to PD-L1,PD-L2 or CTLA4. For example, the anti-PD-1 antibody molecule can beadministered in combination with an anti-CTLA-4 antibody, e.g.,ipilimumab, for example, to treat a cancer (e.g., a cancer chosen from:a melanoma, e.g., a metastatic melanoma; a lung cancer, e.g., anon-small cell lung carcinoma; or a prostate cancer). Exemplaryanti-CTLA4 antibodies include Tremelimumab (IgG2 monoclonal antibodyavailable from Pfizer, formerly known as ticilimumab, CP-675,206); andIpilimumab (CTLA-4 antibody, also known as MDX-010, CAS No.477202-00-9). In one embodiment, the anti-PD-1 antibody molecule isadministered after treatment, e.g., after treatment of a melanoma, withan anti-CTLA4 antibody (e.g., ipilimumab) with or without a BRAFinhibitor (e.g., vemurafenib or dabrafenib). Exemplary doses that can beuse include a dose of anti-PD-1 antibody molecule of about 1 to 10mg/kg, e.g., 3 mg/kg, and a dose of an anti-CTLA-4 antibody, e.g.,ipilimumab, of about 3 mg/kg.

Immune inhibitory molecules, e.g., PD-1 and LAG-3, can regulate, e.g.,synergistically regulate, T-cell function to promote tumoral immuneescape. In another embodiment, the anti-PD-1 antibody molecule isadministered in combination with an anti-LAG-3 antibody or anantigen-binding fragment thereof. In another embodiment, the anti-PD-1antibody molecule is administered in combination with an anti-TIM-3antibody or antigen-binding fragment thereof. In yet other embodiments,the anti-PD-1 antibody molecule is administered in combination with ananti-LAG-3 antibody and an anti-TIM-3 antibody, or antigen-bindingfragments thereof. The combination of antibodies recited herein can beadministered separately, e.g., as separate antibodies, or linked, e.g.,as a bispecific or trispecific antibody molecule. In another embodiment,the anti-PD-1 antibody molecule is administered in combination with aCEACAM inhibitor (e.g., CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor),e.g., an anti-CEACAM antibody molecule. In another embodiment, theanti-PD-1 antibody molecule is administered in combination with aCEACAM-1 inhibitor, e.g., an anti-CEACAM-1 antibody molecule. In anotherembodiment, the anti-PD-1 antibody molecule is administered incombination with a CEACAM-5 inhibitor, e.g., an anti-CEACAM-5 antibodymolecule. In one embodiment, a bispecific antibody that includes ananti-PD-1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody, orantigen-binding fragment thereof, is administered. In certainembodiments, the combination of antibodies recited herein is used totreat a cancer, e.g., a cancer as described herein (e.g., a solidtumor). The efficacy of the aforesaid combinations can be tested inanimal models known in the art. For example, the animal models to testthe synergistic effect of anti-PD-1 and anti-LAG-3 are described, e.g.,in Woo et al. (2012) Cancer Res. 72(4):917-27).

In one embodiment, the inhibitor of CEACAM (e.g., CEACAM-1 and/orCEACAM-5) is an anti-CEACAM antibody molecule. Without wishing to bebound by theory, CEACAM-1 has been described as a ligand and partner ofTIM-3 (see e.g., WO 2014/022332). Synergistic in vivo effect of thecombination of anti-TIM-3 and anti-CEACAM-1 antibodies have beendetected in xenograft cancer models (see e.g., WO 2014/022332). Tumorsare believed to use CEACAM-1 or CEACAM-5 to inhibit the immune system,as described in, e.g., Markel et al. J Immunol. 2002 Mar. 15;168(6):2803-10; Markel et al. J Immunol. 2006 Nov. 1; 177(9):6062-71;Markel et al. Immunology. 2009 February; 126(2):186-200; Markel et al.Cancer Immunol Immunother. 2010 February; 59(2):215-30; Ortenberg et al.Mol Cancer Ther. 2012 June; 11(6):1300-10; Stern et al. J Immunol. 2005Jun. 1; 174(11):6692-701; Zheng et al. PLoS One. 2010 Sep. 2; 5(9). pii:e12529. Thus, CEACAM inhibitors can be used with the otherimmunomodulators described herein (e.g., anti-PD-1 or anti-TIM-3inhibitors) to enhance an immune response against a cancer, e.g.,melanoma, lung cancer (e.g., NSCLC), bladder, colon or ovarian cancer,or other cancers as described herein. In one embodiment, the inhibitorof CEACAM is an anti-CEACAM-1 antibody as described in WO 2010/125571,WO 2013/82366 and WO 2014/022332, e.g., a monoclonal antibody 34B1,26H7, and 5F4 or a recombinant form thereof, as described in, e.g., US2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/52552. In otherembodiments, the anti-CEACAM antibody is an anti-CEACAM-1 and/oranti-CEACAM-5 antibody molecule as described in, e.g., WO 2010/125571,WO 2013/054331 and US 2014/0271618.

In some embodiments, the PD-1 and LAG-3 immune inhibitory molecules(e.g., antibody molecules) are administered in combination with eachother, e.g., to treat cancer. In some embodiments, the patient is apatient who progressed (e.g., experienced tumor growth) during therapywith a PD-1 inhibitor (e.g., an antibody molecule as described herein)and/or a PD-L1 inhibitor (e.g., antibody molecule). In some embodiments,therapy with the PD-1 antibody molecule and/or PD-L1 antibody moleculeis continued, and a LAG-3 immune inhibitory molecule (e.g., antibody) isadded to the therapy.

In some embodiments, the PD-1 and TIM-3 immune inhibitory molecules(e.g., antibody molecules) are administered in combination with eachother, e.g., to treat cancer. In some embodiments, the patient is apatient who progressed (e.g., experienced tumor growth) during therapywith a PD-1 inhibitor (e.g., an antibody molecule as described herein)and/or a PD-L1 inhibitor (e.g., antibody molecule). In some embodiments,therapy with the PD-1 antibody molecule and/or PD-L1 antibody moleculeis continued, and a TIM-3 immune inhibitory molecule (e.g., antibody) isadded to the therapy.

In other embodiments, the anti-PD-1 antibody molecule is administered incombination with a cytokine, e.g., interleukin-21, interleukin-2,interleukin-12, or interleukin-15. In certain embodiments, thecombination of anti-PD-1 antibody molecule and cytokine described hereinis used to treat a cancer, e.g., a cancer as described herein (e.g., asolid tumor or melanoma).

Exemplary immunomodulators that can be used in combination withanti-PD-1 antibody molecules include, but are not limited to, e.g.,afutuzumab (available from Roche®); pegfilgrastim (Neulasta®);lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®), actimid(CC4047); and cytokines, e.g., IL-21 or IRX-2 (mixture of humancytokines including interleukin 1, interleukin 2, and interferon γ, CAS951209-71-5, available from IRX Therapeutics).

In yet other embodiments, the anti-PD-1 antibody molecule is used incombination with an indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor(e.g., INCB24360) in a subject with advanced or metastatic cancer (e.g.,a patient with metastic and recurrent NSCL cancer).

In other embodiments, the anti-PD-1 antibody molecules are administeredto a subject in conjunction with (e.g., before, simultaneously orfollowing) one or more of: bone marrow transplantation, T cell ablativetherapy using chemotherapy agents such as, fludarabine, external-beamradiation therapy (XRT), cyclophosphamide, and/or antibodies such asOKT3 or CAMPATH. In one embodiment, the anti-PD-1 antibody molecules areadministered following B-cell ablative therapy such as agents that reactwith CD20, e.g., Rituxan. For example, in one embodiment, subjects mayundergo standard treatment with high dose chemotherapy followed byperipheral blood stem cell transplantation. In certain embodiments,following the transplant, subjects receive the anti-PD-1 antibodymolecules. In an additional embodiment, the anti-PD-1 antibody moleculesare administered before or following surgery.

Another example of a combination is an anti-PD-1 antibody in combinationwith decarbazine for the treatment of melanoma. Without being bound bytheory, the combined use of PD-1 blockade and chemotherapy is believedto be facilitated by cell death, that is a consequence of the cytotoxicaction of most chemotherapeutic compounds, which can result in increasedlevels of tumor antigen in the antigen presentation pathway. Othercombination therapies that may result in synergy with PD-1 blockadethrough cell death are radiation, surgery, and hormone deprivation. Eachof these protocols creates a source of tumor antigen in the host.Angiogenesis inhibitors may also be combined with PD-1 blockade.Inhibition of angiogenesis leads to tumor cell death which may feedtumor antigen into host antigen presentation pathways.

PD-1 blocking antibodies can also be used in combination with bispecificantibodies. Bispecific antibodies can be used to target two separateantigens. For example anti-Fc receptor/anti tumor antigen (e.g.,Her-2/neu) bispecific antibodies have been used to target macrophages tosites of tumor. This targeting may more effectively activate tumorspecific responses. The T cell arm of these responses would by augmentedby the use of PD-1 blockade. Alternatively, antigen may be delivereddirectly to DCs by the use of bispecific antibodies which bind to tumorantigen and a dendritic cell specific cell surface marker.

Tumors evade host immune surveillance by a large variety of mechanisms.Many of these mechanisms may be overcome by the inactivation of proteinswhich are expressed by the tumors and which are immunosuppressive. Theseinclude among others TGF-beta (Kehrl, J. et al. (1986) J. Exp. Med. 163:1037-1050), IL-10 (Howard, M. & O'Garra, A. (1992) Immunology Today 13:198-200), and Fas ligand (Hahne, M. et al. (1996) Science 274:1363-1365). Antibodies or antigen-binding fragments thereof to each ofthese entities may be used in combination with anti-PD-1 to counteractthe effects of the immunosuppressive agent and favor tumor immuneresponses by the host.

Other antibodies which may be used to activate host immuneresponsiveness can be used in combination with anti-PD-1. These includemolecules on the surface of dendritic cells which activate DC functionand antigen presentation. Anti-CD40 antibodies are able to substituteeffectively for T cell helper activity (Ridge, J. et al. (1998) Nature393: 474-478) and can be used in conjunction with PD-1 antibodies (Ito,N. et al. (2000) Immunobiology 201 (5) 527-40). Antibodies to T cellcostimulatory molecules such as CTLA-4 (e.g., U.S. Pat. No. 5,811,097),OX-40 (Weinberg, A. et al. (2000) Immunol 164: 2160-2169), 4-1BB(Melero, I. et al. (1997) Nature Medicine 3: 682-685 (1997), and ICOS(Hutloff, A. et al. (1999) Nature 397: 262-266) may also provide forincreased levels of T cell activation.

Additional exemplary standard of care treatments are described in thesection entitled “Combination Therapies” below.

In all of the methods described herein, PD-1 blockade can be combinedwith other forms of immunotherapy such as cytokine treatment (e.g.,interferons, GM-CSF, G-CSF, IL-2, IL-21), or bispecific antibodytherapy, which provides for enhanced presentation of tumor antigens (seee.g., Holliger (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak(1994) Structure 2:1121-1123).

Methods of administering the antibody molecules are known in the art andare described below. Suitable dosages of the molecules used will dependon the age and weight of the subject and the particular drug used.Dosages and therapeutic regimens of the anti-PD-1 antibody molecule canbe determined by a skilled artisan. In certain embodiments, theanti-PD-1 antibody molecule is administered by injection (e.g.,subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, e.g.,about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about3 mg/kg. In some embodiments, the anti-PD-1 antibody molecule isadministered at a dose of about 1 mg/kg, about 3 mg/kg, or 10 mg/kg,about 20 mg/kg, about 30 mg/kg, or about 40 mg/kg. In some embodiments,the anti-PD-1 antibody molecule is administered at a dose of about 1-3mg/kg, or about 3-10 mg/kg. In some embodiments, the anti-PD-1 antibodymolecule is administered at a dose of about 0.5-2, 2-4, 2-5, 5-15, or5-20 mg/kg. The dosing schedule can vary from e.g., once a week to onceevery 2, 3, or 4 weeks. In one embodiment, the anti-PD-1 antibodymolecule is administered at a dose from about 10 to 20 mg/kg every otherweek.

The antibody molecules can be used in unconjugated forms or conjugatedto a second agent, e.g., a cytotoxic drug, radioisotope, or a protein,e.g., a protein toxin or a viral protein. This method includes:administering the antibody molecule, alone or conjugated to a cytotoxicdrug, to a subject requiring such treatment. The antibody molecules canbe used to deliver a variety of therapeutic agents, e.g., a cytotoxicmoiety, e.g., a therapeutic drug, a radioisotope, molecules of plant,fungal, or bacterial origin, or biological proteins (e.g., proteintoxins) or particles (e.g., a recombinant viral particles, e.g.; via aviral coat protein), or mixtures thereof.

Additional Combination Therapies

The anti-PD-1 antibody molecule can be used in combination with othertherapies. For example, the combination therapy can include acomposition of the present invention co-formulated with, and/orco-administered with, one or more additional therapeutic agents, e.g.,one or more anti-cancer agents, cytotoxic or cytostatic agents, hormonetreatment, vaccines, and/or other immunotherapies. In other embodiments,the antibody molecules are administered in combination with othertherapeutic treatment modalities, including surgery, radiation,cryosurgery, and/or thermotherapy. Such combination therapies mayadvantageously utilize lower dosages of the administered therapeuticagents, thus avoiding possible toxicities or complications associatedwith the various monotherapies.

By “in combination with,” it is not intended to imply that the therapyor the therapeutic agents must be administered at the same time and/orformulated for delivery together, although these methods of delivery arewithin the scope described herein. The anti-PD-1 antibody molecules canbe administered concurrently with, prior to, or subsequent to, one ormore other additional therapies or therapeutic agents. The anti-PD-1antibody molecule and the other agent or therapeutic protocol can beadministered in any order. In general, each agent will be administeredat a dose and/or on a time schedule determined for that agent. In willfurther be appreciated that the additional therapeutic agent utilized inthis combination may be administered together in a single composition oradministered separately in different compositions. In general, it isexpected that additional therapeutic agents utilized in combination beutilized at levels that do not exceed the levels at which they areutilized individually. In some embodiments, the levels utilized incombination will be lower than those utilized individually.

In certain embodiments, the anti-PD-1 molecules described herein areadministered in combination with one or more other inhibitors of PD-1,PD-L1 and/or PD-L2 known in the art. The antagonist may be an antibody,an antigen binding fragment thereof, an immunoadhesin, a fusion protein,or oligopeptide. In some embodiments, the other anti-PD-1 antibody ischosen from MDX-1106, Merck 3475 or CT-011. In some embodiments, thePD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising anextracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to aconstant region (e.g., an Fc region of an immunoglobulin sequence). Insome embodiments, the PD-1 inhibitor is AMP-224. In some embodiments,the PD-L1 inhibitor is anti-PD-L1 antibody. In some embodiments, theanti-PD-L1 binding antagonist is chosen from YW243.55.570, MPDL3280A,MEDI-4736, MSB-0010718C, or MDX-1105. MDX-1105, also known asBMS-936559, is an anti-PD-L1 antibody described in WO2007/005874.Antibody YW243.55.570 (heavy and light chain variable region sequencesshown in SEQ ID Nos. 20 and 21, respectively) is an anti-PD-L1 describedin WO 2010/077634.

MDX-1106, also known as MDX-1106-04, ONO-4538 or BMS-936558, is ananti-PD-1 antibody described in WO2006/121168. Merck 3745, also known asMK-3475 or SCH-900475, is an anti-PD-1 antibody described inWO2009/114335. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1kmonoclonal antibody that binds to PD-1. Pidilizumab and other humanizedanti-PD-1 monoclonal antibodies are disclosed in WO2009/101611. In otherembodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab(Trade name Keytruda formerly lambrolizumab also known as MK-3475)disclosed, e.g., in Hamid, O. et al. (2013) New England Journal ofMedicine 369 (2): 134-44. AMP-224 (B7-DCIg; Amplimmune; e.g., disclosedin WO2010/027827 and WO2011/066342), is a PD-L2 Fc fusion solublereceptor that blocks the interaction between PD-1 and B7-H1. Otheranti-PD-1 antibodies include AMP 514 (Amplimmune), among others, e.g.,anti-PD-1 antibodies disclosed in U.S. Pat. No. 8,609,089, US2010028330, and/or US 20120114649.

In some embodiments, the other anti-PD-1 antibody is MDX-1106.Alternative names for MDX-1106 include MDX-1106-04, ONO-4538, BMS-936558or Nivolumab. In some embodiments, the anti-PD-1 antibody is Nivolumab(CAS Registry Number: 946414-94-4).

Nivolumab (also referred to as BMS-936558 or MDX1106; Bristol-MyersSquibb) is a fully human IgG4 monoclonal antibody which specificallyblocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodiesthat specifically bind to PD-1 are disclosed in U.S. Pat. No. 8,008,449and WO2006/121168. Lambrolizumab (also referred to as pembrolizumab orMK03475; Merck) is a humanized IgG4 monoclonal antibody that binds toPD-1. Pembrolizumab and other humanized anti-PD-1 antibodies aredisclosed in U.S. Pat. No. 8,354,509 and WO2009/114335. MDPL3280A(Genentech/Roche) is a human Fc optimized IgG1 monoclonal antibody thatbinds to PD-L1. MDPL3280A and other human monoclonal antibodies to PD-L1are disclosed in U.S. Pat. No. 7,943,743 and U.S Publication No.:20120039906. Other anti-PD-L1 binding agents include YW243.55.570 (heavyand light chain variable regions are shown in SEQ ID NOs 20 and 21 inWO2010/077634) and MDX-1105 (also referred to as BMS-936559, and, e.g.,anti-PD-L1 binding agents disclosed in WO2007/005874).

Cancer Therapies

Exemplary combinations of anti-PD-1 antibody molecules (alone or incombination with other stimulatory agents) and standard of care forcancer, include at least the following. In certain embodiments, theanti-PD-1 antibody molecule, e.g., the anti-PD-1 antibody moleculedescribed herein, is used in combination with a standard of cancer carechemotherapeutic agent including, but not limited to, anastrozole(Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®),busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine(Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin(Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin(Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® orNeosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabineliposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), dactinomycin(Actinomycin D, Cosmegan), daunorubicin hydrochloride (Cerubidine®),daunorubicin citrate liposome injection (DaunoXome®), dexamethasone,docetaxel (Taxotere®), doxorubicin hydrochloride (Adriamycin®, Rubex®),etoposide (Vepesid®), fludarabine phosphate (Fludara®), 5-fluorouracil(Adrucil®, Efudex®), flutamide (Eulexin®), tezacitibine, Gemcitabine(difluorodeoxycitidine), hydroxyurea (Hydrea®), Idarubicin (Idamycin®),ifosfamide (IFEX®), irinotecan (Camptosar®), L-asparaginase (ELSPAR®),leucovorin calcium, melphalan (Alkeran®), 6-mercaptopurine(Purinethol®), methotrexate (Folex®), mitoxantrone (Novantrone®),mylotarg, paclitaxel (Taxol®), phoenix (Yttrium90/MX-DTPA), pentostatin,polifeprosan 20 with carmustine implant (Gliadel®), tamoxifen citrate(Nolvadex®), teniposide (Vumon®), 6-thioguanine, thiotepa, tirapazamine(Tirazone®), topotecan hydrochloride for injection (Hycamptin®),vinblastine (Velban®), vincristine (Oncovin®), vinorelbine (Navelbine®),Ibrutinib, idelalisib, and brentuximab vedotin.

Exemplary alkylating agents include, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes): uracil mustard (Aminouracil Mustard®, Chlorethaminacil®,Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracilnitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®,Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®,Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide(Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman(Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®),triethylenethiophosphoramine, Temozolomide (Temodar®), thiotepa(Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®),lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine(DTIC-Dome®). Additional exemplary alkylating agents include, withoutlimitation, Oxaliplatin (Eloxatin®); Temozolomide (Temodar® andTemodal®); Dactinomycin (also known as actinomycin-D, Cosmegen®);Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard,Alkeran®); Altretamine (also known as hexamethylmelamine (HMM),Hexalen®); Carmustine (BiCNU®); Bendamustine (Treanda®); Busulfan(Busulfex® and Myleran®); Carboplatin (Paraplatin®); Lomustine (alsoknown as CCNU, CeeNU®); Cisplatin (also known as CDDP, Platinol® andPlatinol®-AQ); Chlorambucil (Leukeran®); Cyclophosphamide (Cytoxan® andNeosar®); Dacarbazine (also known as DTIC, DIC and imidazolecarboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine(HMM), Hexalen®); Ifosfamide (Ifex®); Prednumustine; Procarbazine(Matulane®); Mechlorethamine (also known as nitrogen mustard, mustineand mechloroethamine hydrochloride, Mustargen®); Streptozocin(Zanosar®); Thiotepa (also known as thiophosphoamide, TESPA and TSPA,Thioplex®); Cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®,Revimmune®); and Bendamustine HCl (Treanda®)).

Exemplary anthracyclines include, e.g., doxorubicin (Adriamycin® andRubex®); bleomycin (Lenoxane®); daunorubicin (dauorubicin hydrochloride,daunomycin, and rubidomycin hydrochloride, Cerubidine®); daunorubicinliposomal (daunorubicin citrate liposome, DaunoXome®); mitoxantrone(DHAD, Novantrone®); epirubicin (Ellence™); idarubicin (Idamycin®,Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin;ravidomycin; and desacetylravidomycin.

Exemplary vinca alkaloids that can be used in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), include, but ate not limited to, vinorelbine tartrate(Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®));vinblastine (also known as vinblastine sulfate, vincaleukoblastine andVLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®).

Exemplary proteosome inhibitors that can be used in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), include, but ate not limited to, bortezomib (Velcade®);carfilzomib (PX-171-007,(S)-4-Methyl-N—((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutanamido)-pentanamide);marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib(CEP-18770); andO-Methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide(ONX-0912).

In some embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), in combination with atyrosine kinase inhibitor (e.g., a receptor tyrosine kinase (RTK)inhibitor). Exemplary tyrosine kinase inhibitor include, but are notlimited to, an epidermal growth factor (EGF) pathway inhibitor (e.g., anepidermal growth factor receptor (EGFR) inhibitor), a vascularendothelial growth factor (VEGF) pathway inhibitor (e.g., a vascularendothelial growth factor receptor (VEGFR) inhibitor (e.g., a VEGFR-1inhibitor, a VEGFR-2 inhibitor, a VEGFR-3 inhibitor)), a plateletderived growth factor (PDGF) pathway inhibitor (e.g., a platelet derivedgrowth factor receptor (PDGFR) inhibitor (e.g., a PDGFR-ß inhibitor)), aRAF-1 inhibitor, a KIT inhibitor and a RET inhibitor. In someembodiments, the anti-cancer agent used in combination with the hedgehoginhibitor is selected from the group consisting of: axitinib (AG013736),bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib(SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®),imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®),lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®),semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib(PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK),trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®),cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®),nilotinib (TASIGNA®), sorafenib (NEXAVAR®), alemtuzumab (CAMPATH®),gemtuzumab ozogamicin (MYLOTARG®), ENMD-2076, PCI-32765, AC220,dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523,PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154,CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, XL228,AEE788, AG-490, AST-6, BMS-599626, CUDC-101, PD153035, pelitinib(EKB-569), vandetanib (zactima), WZ3146, WZ4002, WZ8040, ABT-869(linifanib), AEE788, AP24534 (ponatinib), AV-951(tivozanib), axitinib,BAY 73-4506 (regorafenib), brivanib alaninate (BMS-582664), brivanib(BMS-540215), cediranib (AZD2171), CHIR-258 (dovitinib), CP 673451,CYC116, E7080, Ki8751, masitinib (AB1010), MGCD-265, motesanibdiphosphate (AMG-706), MP-470, OSI-930, Pazopanib Hydrochloride,PD173074, Sorafenib Tosylate (Bay 43-9006), SU 5402, TSU-68(SU6668),vatalanib, XL880 (GSK1363089, EXEL-2880). Selected tyrosine kinaseinhibitors are chosen from sunitinib, erlotinib, gefitinib, orsorafenib.

In certain embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), in combination with aVascular Endothelial Growth Factor (VEGF) receptor inhibitors, includingbut not limited to, Bevacizumab (Avastin®), axitinib (Inlyta®); Brivanibalaninate (BMS-582664,(S)—((R)-1-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate);Sorafenib (Nexavar®); Pazopanib (Votrient®); Sunitinib malate (Sutent®);Cediranib (AZD2171, CAS 288383-20-1); Vargatef (BIBF1120, CAS928326-83-4); Foretinib (GSK1363089); Telatinib (BAY57-9352, CAS332012-40-5); Apatinib (YN968D1, CAS 811803-05-1); Imatinib (Gleevec®);Ponatinib (AP24534, CAS 943319-70-8); Tivozanib (AV951, CAS475108-18-0); Regorafenib (BAY73-4506, CAS 755037-03-7); Vatalanibdihydrochloride (PTK787, CAS 212141-51-0); Brivanib (BMS-540215, CAS649735-46-6); Vandetanib (Caprelsa® or AZD6474); Motesanib diphosphate(AMG706, CAS 857876-30-3,N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridinylmethyl)amino]-3-pyridinecarboxamide,described in PCT Publication No. WO 02/066470); Dovitinib dilactic acid(TKI258, CAS 852433-84-2); Linfanib (ABT869, CAS 796967-16-3);Cabozantinib (XL184, CAS 849217-68-1); Lestaurtinib (CAS 111358-88-4);N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide(BMS38703, CAS 345627-80-7);(3R,4R)-4-Amino-1-((4-(β-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-3-ol(BMS690514);N-(3,4-Dichloro-2-fluorophenyl)-6-methoxy-7-[[(3aα,5β,6aα)-octahydro-2-methylcyclopenta[c]pyrrol-5-yl]methoxy]-4-quinazolinamine(XL647, CAS 781613-23-8);4-Methyl-3-[[1-methyl-6-β-pyridinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino]-N-[3-(trifluoromethyl)phenyl]-benzamide(BHG712, CAS 940310-85-0); and Aflibercept (Eylea®).

Exemplary anti-VEGF antibodies include, but are not limited to, amonoclonal antibody that binds to the same epitope as the monoclonalanti-VEGF antibody A4.6.1 produced by hybridoma ATCC HB 10709; arecombinant humanized anti-VEGF monoclonal antibody generated accordingto Presta et al. (1997) Cancer Res. 57:4593-4599. In one embodiment, theanti-VEGF antibody is Bevacizumab (BV), also known as rhuMAb VEGF orAVASTIN®. It comprises mutated human IgG1 framework regions andantigen-binding complementarity-determining regions from the murineanti-hVEGF monoclonal antibody A.4.6.1 that blocks binding of human VEGFto its receptors. Bevacizumab and other humanized anti-VEGF antibodiesare further described in U.S. Pat. No. 6,884,879 issued Feb. 26, 2005.Additional antibodies include the G6 or B20 series antibodies (e.g.,G6-31, B20-4.1), as described in PCT Publication No. WO2005/012359, PCTPublication No. WO2005/044853, the contents of these patent applicationsare expressly incorporated herein by reference. For additionalantibodies see U.S. Pat. Nos. 7,060,269, 6,582,959, 6,703,020,6,054,297, WO98/45332, WO 96/30046, WO94/10202, EP 0666868B1, U.S.Patent Application Publication Nos. 2006009360, 20050186208,20030206899, 20030190317, 20030203409, and 20050112126; and Popkov etal, Journal of Immunological Methods 288: 149-164 (2004). Otherantibodies include those that bind to a functional epitope on human VEGFcomprising of residues F17, Ml 8, D19, Y21, Y25, Q89, 191, K101, El 03,and C104 or, alternatively, comprising residues F17, Y21, Q22, Y25, D63,183 and Q89.

In some embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), in combination with a PI3Kinhibitor. In one embodiment, the PI3K inhibitor is an inhibitor ofdelta and gamma isoforms of PI3K. Exemplary PI3K inhibitors that can beused in combination are described in, e.g., WO 2010/036380, WO2010/006086, WO 09/114870, WO 05/113556, GSK 2126458, GDC-0980,GDC-0941, Sanofi XL147, XL756, XL147, PF-46915032, BKM 120, CAL-101, CAL263, SF1126, PX-886, and a dual PI3K inhibitor (e.g., Novartis BEZ235).

In some embodiments, the anti-PD-1 antibody molecules described hereinis used, alone or in combination with another immunomodulator (e.g., ananti-LAG-3, anti-PD-L1 or anti-TIM-3 antibody molecule), in combinationwith a mTOR inhibitor, e.g., one or more mTOR inhibitors chosen from oneor more of rapamycin, temsirolimus (TORISEL®), AZD8055, BEZ235, BGT226,XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794,WYE-354, Palomid 529 (P529), PF-04691502, or PKI-587. ridaforolimus(formally known as deferolimus, (1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0^(4,9)]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669, and described inPCT Publication No. WO 03/064383); everolimus (Afinitor® or RAD001);rapamycin (AY22989, Sirolimus®); simapimod (CAS 164301-51-3);emsirolimus,(5-{2,4-Bis[(3S)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl}-2-methoxyphenyl)methanol(AZD8055);2-Amino-8-[trans-4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxy-3-pyridinyl)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one(PF04691502, CAS 1013101-36-4); andN²-[1,4-dioxo-4-[[4-(4-oxo-8-phenyl-4H-1-benzopyran-2-yl)morpholinium-4-yl]methoxy]butyl]-L-arginylglycyl-L-α-aspartylL-serine-(SEQ ID NO: 237), inner salt (SF1126, CAS 936487-67-1), and XL765.

In some embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), in combination with a BRAFinhibitor, e.g., GSK2118436, RG7204, PLX4032, GDC-0879, PLX4720, andsorafenib tosylate (Bay 43-9006).

In some embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), in combination with a MEKinhibitor. In some embodiments, the combination of the anti-PD-1antibody and the MEK inhibitor is used to treat a cancer (e.g., a cancerdescribed herein). In some embodiments, the cancer treated with thecombination is chosen from a melanoma, a colorectal cancer, a non-smallcell lung cancer, an ovarian cancer, a breast cancer, a prostate cancer,a pancreatic cancer, a hematological malignancy or a renal cellcarcinoma. In certain embodiments, the cancer includes a BRAF mutation(e.g., a BRAF V600E mutation), a BRAF wildtype, a KRAS wildtype or anactivating KRAS mutation. The cancer may be at an early, intermediate orlate stage. Any MEK inhibitor can be used in combination including, butnot limited to, ARRY-142886, G02442104 (also known as GSK1120212),RDEA436, RDEA119/BAY 869766, AS703026, G00039805 (also known as AZD-6244or selumetinib), BIX 02188, BIX 02189, CI-1040 (PD-184352), PD0325901,PD98059, U0126, GDC-0973 (Methanone,[3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl][3-hydroxy-3-(25)-2-piperidinyl-1-azetidinyl]-),G-38963, G02443714 (also known as AS703206), or a pharmaceuticallyacceptable salt or solvate thereof. Additional examples of MEKinhibitors are disclosed in WO 2013/019906, WO 03/077914, WO2005/121142, WO 2007/04415, WO 2008/024725 and WO 2009/085983, thecontents of which are incorporated herein by reference.

In some embodiments, the anti-PD-1 antibody molecule, e.g., theanti-PD-1 antibody molecule described herein, is used, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), in combination with a JAK2inhibitor, e.g., CEP-701, INCB18424, CP-690550 (tasocitinib).

In some embodiments, the pharmaceutical composition described herein isused, alone or in combination with another immunomodulator (e.g., ananti-LAG-3, anti-PD-L1 or anti-TIM-3 antibody molecule), in combinationwith paclitaxel or a paclitaxel agent, e.g., TAXOL®, protein-boundpaclitaxel (e.g., ABRAXANE®). Exemplary paclitaxel agents include, butare not limited to, nanoparticle albumin-bound paclitaxel (ABRAXANE,marketed by Abraxis Bioscience), docosahexaenoic acid bound-paclitaxel(DHA-paclitaxel, Taxoprexin, marketed by Protarga), polyglutamatebound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX,marketed by Cell Therapeutic), the tumor-activated prodrug (TAP), ANG105(Angiopep-2 bound to three molecules of paclitaxel, marketed byImmunoGen), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizingpeptide EC-1; see L1 et al., Biopolymers (2007) 87:225-230), andglucose-conjugated paclitaxel (e.g., 2′-paclitaxel methyl2-glucopyranosyl succinate, see Liu et al., Bioorganic & MedicinalChemistry Letters (2007) 17:617-620).

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” refersto radiation therapy delivered by a spatially confined radioactivematerial inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Anti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), can be administered in combination with one or more of theexisting modalities for treating cancers, including, but not limited to:surgery; radiation therapy (e.g., external-beam therapy which involvesthree dimensional, conformal radiation therapy where the field ofradiation is designed, local radiation (e.g., radiation directed to apreselected target or organ), or focused radiation). Focused radiationcan be selected from the group consisting of stereotactic radiosurgery,fractionated stereotactic radiosurgery, and intensity-modulatedradiation therapy. The focused radiation can have a radiation sourceselected from the group consisting of a particle beam (proton),cobalt-60 (photon), and a linear accelerator (x-ray), e.g., as describedin WO 2012/177624.

In certain embodiments, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is administered incombination with an antibody against a Killer-cell Immunoglobulin-likeReceptors (also referred to herein as an “anti-KIR antibody”), a pan-KIRantibody, an anti-NKG2D antibody, and an anti-MICA antibody. In certainembodiments, the combination of anti-PD-1 antibody molecule and anti-KIRantibody, pan-KIR antibody, or an anti-NKG2D antibody described hereinis used to treat a cancer, e.g., a cancer as described herein (e.g., asolid tumor, e.g., an advanced solid tumor).

In one embodiment, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is administered incombination with a cellular immunotherapy (e.g., Provenge (e.g.,Sipuleucel)), and optionally in combination with cyclophosphamide. Incertain embodiments, the combination of anti-PD-1 antibody molecule,Provenge and/or cyclophosphamide is used to treat a cancer, e.g., acancer as described herein (e.g., a prostate cancer, e.g., an advancedprostate cancer).

In another embodiment, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is administered incombination with a vaccine, e.g., a dendritic cell renal carcinoma(DC-RCC) vaccine. In certain embodiments, the combination of anti-PD-1antibody molecule and the DC-RCC vaccine is used to treat a cancer,e.g., a cancer as described herein (e.g., a renal carcinoma, e.g.,metastatic renal cell carcinoma (RCC) or clear cell renal cell carcinoma(CCRCC)).

In yet another embodiment, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is administered incombination with chemotherapy, and/or immunotherapy. For example, theanti-PD-1 antibody molecule can be used to treat a myeloma, alone or incombination with one or more of: chemotherapy or other anti-canceragents (e.g., thalidomide analogs, e.g., lenalidomide), an anti-TIM-3antibody, tumor antigen-pulsed dendritic cells, fusions (e.g.,electrofusions) of tumor cells and dendritic cells, or vaccination withimmunoglobulin idiotype produced by malignant plasma cells. In oneembodiment, the anti-PD-1 antibody molecule is used in combination withan anti-TIM-3 antibody to treat a myeloma, e.g., a multiple myeloma.

In one embodiment, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is used in combination withchemotherapy to treat a lung cancer, e.g., non-small cell lung cancer.In one embodiment, the anti-PD-1 antibody molecule is used with platinumdoublet therapy to treat lung cancer.

In yet another embodiment, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is used to treat a renalcancer, e.g., renal cell carcinoma (RCC) (e.g., clear cell renal cellcarcinoma (CCRCC) or metastatic RCC. The anti-PD-1 antibody molecule canbe administered in combination with one or more of: an immune-basedstrategy (e.g., interleukin-2 or interferon-α), a targeted agent (e.g.,a VEGF inhibitor such as a monoclonal antibody to VEGF); a VEGF tyrosinekinase inhibitor such as sunitinib, sorafenib, axitinib and pazopanib;an RNAi inhibitor), or an inhibitor of a downstream mediator of VEGFsignaling, e.g., an inhibitor of the mammalian target of rapamycin(mTOR), e.g., everolimus and temsirolimus.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules described herein, alone or in combinationwith another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1 oranti-TIM-3 antibody molecule), for treatment of pancreatic cancerincludes, but is not limited to, a chemotherapeutic agent, e.g.,paclitaxel or a paclitaxel agent (e.g., a paclitaxel formulation such asTAXOL, an albumin-stabilized nanoparticle paclitaxel formulation (e.g.,ABRAXANE) or a liposomal paclitaxel formulation); gemcitabine (e.g.,gemcitabine alone or in combination with AXP107-11); otherchemotherapeutic agents such as oxaliplatin, 5-fluorouracil,capecitabine, rubitecan, epirubicin hydrochloride, NC-6004, cisplatin,docetaxel (e.g., TAXOTERE), mitomycin C, ifosfamide; interferon;tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g., erlotinib,panitumumab, cetuximab, nimotuzumab); HER2/neu receptor inhibitor (e.g.,trastuzumab); dual kinase inhibitor (e.g., bosutinib, saracatinib,lapatinib, vandetanib); multikinase inhibitor (e.g., sorafenib,sunitinib, XL184, pazopanib); VEGF inhibitor (e.g., bevacizumab, AV-951,brivanib); radioimmunotherapy (e.g., XR303); cancer vaccine (e.g., GVAX,survivin peptide); COX-2 inhibitor (e.g., celecoxib); IGF-1 receptorinhibitor (e.g., AMG 479, MK-0646); mTOR inhibitor (e.g., everolimus,temsirolimus); IL-6 inhibitor (e.g., CNTO 328); cyclin-dependent kinaseinhibitor (e.g., P276-00, UCN-01); Altered Energy Metabolism-Directed(AEMD) compound (e.g., CPI-613); HDAC inhibitor (e.g., vorinostat);TRAIL receptor 2 (TR-2) agonist (e.g., conatumumab); MEK inhibitor(e.g., AS703026, selumetinib, GSK1120212); Raf/MEK dual kinase inhibitor(e.g., RO5126766); Notch signaling inhibitor (e.g., MK0752); monoclonalantibody-antibody fusion protein (e.g., L19IL2); curcumin; HSP90inhibitor (e.g., tanespimycin, STA-9090); rIL-2; denileukin diftitox;topoisomerase 1 inhibitor (e.g., irinotecan, PEP02); statin (e.g.,simvastatin); Factor VIIa inhibitor (e.g., PCI-27483); AKT inhibitor(e.g., RX-0201); hypoxia-activated prodrug (e.g., TH-302); metforminhydrochloride, gamma-secretase inhibitor (e.g., RO4929097);ribonucleotide reductase inhibitor (e.g., 3-AP); immunotoxin (e.g.,HuC242-DM4); PARP inhibitor (e.g., KU-0059436, veliparib); CTLA-4inhbitor (e.g., CP-675,206, ipilimumab); AdV-tk therapy; proteasomeinhibitor (e.g., bortezomib (Velcade), NPI-0052); thiazolidinedione(e.g., pioglitazone); NPC-1C; Aurora kinase inhibitor (e.g.,R763/AS703569), CTGF inhibitor (e.g., FG-3019); siG12D LODER; andradiation therapy (e.g., tomotherapy, stereotactic radiation, protontherapy), surgery, and a combination thereof. In certain embodiments, acombination of paclitaxel or a paclitaxel agent, and gemcitabine can beused with the anti-PD-1 antibody molecules described herein.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of small cell lung cancer includes, but is notlimited to, a chemotherapeutic agent, e.g., etoposide, carboplatin,cisplatin, oxaliplatin, irinotecan, topotecan, gemcitabine, liposomalSN-38, bendamustine, temozolomide, belotecan, NK012, FR901228,flavopiridol); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g.,erlotinib, gefitinib, cetuximab, panitumumab); multikinase inhibitor(e.g., sorafenib, sunitinib); VEGF inhibitor (e.g., bevacizumab,vandetanib); cancer vaccine (e.g., GVAX); Bcl-2 inhibitor (e.g.,oblimersen sodium, ABT-263); proteasome inhibitor (e.g., bortezomib(Velcade), NPI-0052), paclitaxel or a paclitaxel agent; docetaxel; IGF-1receptor inhibitor (e.g., AMG 479); HGF/SF inhibitor (e.g., AMG 102,MK-0646); chloroquine; Aurora kinase inhibitor (e.g., MLN8237);radioimmunotherapy (e.g., TF2); HSP90 inhibitor (e.g., tanespimycin,STA-9090); mTOR inhibitor (e.g., everolimus); Ep-CAM-/CD3-bispecificantibody (e.g., MT110); CK-2 inhibitor (e.g., CX-4945); HDAC inhibitor(e.g., belinostat); SMO antagonist (e.g., BMS 833923); peptide cancervaccine, and radiation therapy (e.g., intensity-modulated radiationtherapy (IMRT), hypofractionated radiotherapy, hypoxia-guidedradiotherapy), surgery, and combinations thereof. An example of suitabletherapeutics for use in combination with the anti-PD-1 antibodymolecules, alone or in combination with another immunomodulator (e.g.,an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibody molecule), fortreatment of non-small cell lung cancer includes, but is not limited to,a chemotherapeutic agent, e.g., vinorelbine, cisplatin, docetaxel,pemetrexed disodium, etoposide, gemcitabine, carboplatin, liposomalSN-38, TLK286, temozolomide, topotecan, pemetrexed disodium,azacitidine, irinotecan, tegafur-gimeracil-oteracil potassium,sapacitabine); tyrosine kinase inhibitor (e.g., EGFR inhibitor (e.g.,erlotinib, gefitinib, cetuximab, panitumumab, necitumumab, PF-00299804,nimotuzumab, RO5083945), MET inhibitor (e.g., PF-02341066, ARQ 197),PI3K kinase inhibitor (e.g., XL147, GDC-0941), Raf/MEK dual kinaseinhibitor (e.g., RO5126766), PI3K/mTOR dual kinase inhibitor (e.g.,XL765), SRC inhibitor (e.g., dasatinib), dual inhibitor (e.g., BIBW2992, GSK1363089, ZD6474, AZD0530, AG-013736, lapatinib, MEHD7945A,linifanib), multikinase inhibitor (e.g., sorafenib, sunitinib,pazopanib, AMG 706, XL184, MGCD265, BMS-690514, R935788), VEGF inhibitor(e.g., endostar, endostatin, bevacizumab, cediranib, BIBF 1120,axitinib, tivozanib, AZD2171), cancer vaccine (e.g., BLP25 liposomevaccine, GVAX, recombinant DNA and adenovirus expressing L523S protein),Bcl-2 inhibitor (e.g., oblimersen sodium), proteasome inhibitor (e.g.,bortezomib, carfilzomib, NPI-0052, MLN9708), paclitaxel or a paclitaxelagent, docetaxel, IGF-1 receptor inhibitor (e.g., cixutumumab, MK-0646,OSI 906, CP-751,871, BIIB022), hydroxychloroquine, HSP90 inhibitor(e.g., tanespimycin, STA-9090, AUY922, XL888), mTOR inhibitor (e.g.,everolimus, temsirolimus, ridaforolimus), Ep-CAM-/CD3-bispecificantibody (e.g., MT110), CK-2 inhibitor (e.g., CX-4945), HDAC inhibitor(e.g., MS 275, LBH589, vorinostat, valproic acid, FR901228), DHFRinhibitor (e.g., pralatrexate), retinoid (e.g., bexarotene, tretinoin),antibody-drug conjugate (e.g., SGN-15), bisphosphonate (e.g., zoledronicacid), cancer vaccine (e.g., belagenpumatucel-L), low molecular weightheparin (LMWH) (e.g., tinzaparin, enoxaparin), GSK1572932A, melatonin,talactoferrin, dimesna, topoisomerase inhibitor (e.g., amrubicin,etoposide, karenitecin), nelfinavir, cilengitide, ErbB3 inhibitor (e.g.,MM-121, U3-1287), survivin inhibitor (e.g., YM155, LY2181308), eribulinmesylate, COX-2 inhibitor (e.g., celecoxib), pegfilgrastim, Polo-likekinase 1 inhibitor (e.g., BI 6727), TRAIL receptor 2 (TR-2) agonist(e.g., CS-1008), CNGRC peptide (SEQ ID NO: 225)-TNF alpha conjugate,dichloroacetate (DCA), HGF inhibitor (e.g., SCH 900105), SAR240550,PPAR-gamma agonist (e.g., CS-7017), gamma-secretase inhibitor (e.g.,RO4929097), epigenetic therapy (e.g., 5-azacitidine), nitroglycerin, MEKinhibitor (e.g., AZD6244), cyclin-dependent kinase inhibitor (e.g.,UCN-01), cholesterol-Fus1, antitubulin agent (e.g., E7389),farnesyl-OH-transferase inhibitor (e.g., lonafarnib), immunotoxin (e.g.,BB-10901, SS1 (dsFv) PE38), fondaparinux, vascular-disrupting agent(e.g., AVE8062), PD-L1 inhibitor (e.g., MDX-1105, MDX-1106),beta-glucan, NGR-hTNF, EMD 521873, MEK inhibitor (e.g., GSK1120212),epothilone analog (e.g., ixabepilone), kinesin-spindle inhibitor (e.g.,4SC-205), telomere targeting agent (e.g., KML-001), P70 pathwayinhibitor (e.g., LY2584702), AKT inhibitor (e.g., MK-2206), angiogenesisinhibitor (e.g., lenalidomide), Notch signaling inhibitor (e.g.,OMP-21M18), radiation therapy, surgery, and combinations thereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of ovarian cancer includes, but is not limitedto, a chemotherapeutic agent (e.g., paclitaxel or a paclitaxel agent;docetaxel; carboplatin; gemcitabine; doxorubicin; topotecan; cisplatin;irinotecan, TLK286, ifosfamide, olaparib, oxaliplatin, melphalan,pemetrexed disodium, SJG-136, cyclophosphamide, etoposide, decitabine);ghrelin antagonist (e.g., AEZS-130), immunotherapy (e.g., APC8024,oregovomab, OPT-821), tyrosine kinase inhibitor (e.g., EGFR inhibitor(e.g., erlotinib), dual inhibitor (e.g., E7080), multikinase inhibitor(e.g., AZD0530, JI-101, sorafenib, sunitinib, pazopanib), ON 01910.Na),VEGF inhibitor (e.g., bevacizumab, BIBF 1120, cediranib, AZD2171), PDGFRinhibitor (e.g., IMC-3G3), paclitaxel, topoisomerase inhibitor (e.g.,karenitecin, Irinotecan), HDAC inhibitor (e.g., valproate, vorinostat),folate receptor inhibitor (e.g., farletuzumab), angiopoietin inhibitor(e.g., AMG 386), epothilone analog (e.g., ixabepilone), proteasomeinhibitor (e.g., carfilzomib), IGF-1 receptor inhibitor (e.g., OSI 906,AMG 479), PARP inhibitor (e.g., veliparib, AG014699, iniparib, MK-4827),Aurora kinase inhibitor (e.g., MLN8237, ENMD-2076), angiogenesisinhibitor (e.g., lenalidomide), DHFR inhibitor (e.g., pralatrexate),radioimmunotherapeutic agent (e.g., Hu3S193), statin (e.g., lovastatin),topoisomerase 1 inhibitor (e.g., NKTR-102), cancer vaccine (e.g., p53synthetic long peptides vaccine, autologous OC-DC vaccine), mTORinhibitor (e.g., temsirolimus, everolimus), BCR/ABL inhibitor (e.g.,imatinib), ET-A receptor antagonist (e.g., ZD4054), TRAIL receptor 2(TR-2) agonist (e.g., CS-1008), HGF/SF inhibitor (e.g., AMG 102),EGEN-001, Polo-like kinase 1 inhibitor (e.g., BI 6727), gamma-secretaseinhibitor (e.g., RO4929097), Wee-1 inhibitor (e.g., MK-1775),antitubulin agent (e.g., vinorelbine, E7389), immunotoxin (e.g.,denileukin diftitox), SB-485232, vascular-disrupting agent (e.g.,AVE8062), integrin inhibitor (e.g., EMD 525797), kinesin-spindleinhibitor (e.g., 4SC-205), revlimid, HER2 inhibitor (e.g., MGAH22),ErrB3 inhibitor (e.g., MM-121), radiation therapy; and combinationsthereof.

In one exemplary embodiment, the anti-PD-1 antibody molecule, alone orin combination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is used to treat a myeloma,alone or in combination with one or more of: chemotherapy or otheranti-cancer agents (e.g., thalidomide analogs, e.g., lenalidomide), HSCT(Cook, R. (2008) J Manag Care Pharm. 14(7 Suppl):19-25), an anti-TIM-3antibody (Hallett, W H D et al. (2011) J of American Society for Bloodand Marrow Transplantation 17(8):1133-145), tumor antigen-pulseddendritic cells, fusions (e.g., electrofusions) of tumor cells anddendritic cells, or vaccination with immunoglobulin idiotype produced bymalignant plasma cells (reviewed in Yi, Q. (2009) Cancer J.15(6):502-10).

In yet another embodiment, the anti-PD-1 antibody molecule, alone or incombination with another immunomodulator (e.g., an anti-LAG-3,anti-PD-L1 or anti-TIM-3 antibody molecule), is used to treat a renalcancer, e.g., renal cell carcinoma (RCC) or metastatic RCC. Theanti-PD-1 antibody molecule can be administered in combination with oneor more of: an immune-based strategy (e.g., interleukin-2 orinterferon-α), a targeted agent (e.g., a VEGF inhibitor such as amonoclonal antibody to VEGF, e.g., bevacizumab (Rini, B. I. et al.(2010) J. Clin. Oncol. 28(13):2137-2143)); a VEGF tyrosine kinaseinhibitor such as sunitinib, sorafenib, axitinib and pazopanib (reviewedin Pal. S. K. et al. (2014) Clin. Advances in Hematology & Oncology12(2):90-99)); an RNAi inhibitor), or an inhibitor of a downstreammediator of VEGF signaling, e.g., an inhibitor of the mammalian targetof rapamycin (mTOR), e.g., everolimus and temsirolimus (Hudes, G. et al.(2007) N. Engl. J. Med. 356(22):2271-2281, Motzer, R. J. et al. (2008)Lancet 372: 449-456).

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules described herein, alone or in combinationwith another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1 oranti-TIM-3 antibody molecule), for treatment of chronic myelogenousleukemia (AML) according to the invention includes, but is not limitedto, a chemotherapeutic (e.g., cytarabine, hydroxyurea, clofarabine,melphalan, thiotepa, fludarabine, busulfan, etoposide, cordycepin,pentostatin, capecitabine, azacitidine, cyclophosphamide, cladribine,topotecan), tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g.,imatinib, nilotinib), ON 01910.Na, dual inhibitor (e.g., dasatinib,bosutinib), multikinase inhibitor (e.g., DCC-2036, ponatinib, sorafenib,sunitinib, RGB-286638)), interferon alfa, steroids, apoptotic agent(e.g., omacetaxine mepesuccinat), immunotherapy (e.g., allogeneic CD4+memory Thl-like T cells/microparticle-bound anti-CD3/anti-CD28,autologous cytokine induced killer cells (CIK), AHN-12), CD52 targetingagent (e.g., alemtuzumab), HSP90 inhibitor (e.g., tanespimycin,STA-9090, AUY922, XL888), mTOR inhibitor (e.g., everolimus), SMOantagonist (e.g., BMS 833923), ribonucleotide reductase inhibitor (e.g.,3-AP), JAK-2 inhibitor (e.g., INCB018424), Hydroxychloroquine, retinoid(e.g., fenretinide), cyclin-dependent kinase inhibitor (e.g., UCN-01),HDAC inhibitor (e.g., belinostat, vorinostat, JNJ-26481585), PARPinhibitor (e.g., veliparib), MDM2 antagonist (e.g., RO5045337), Aurora Bkinase inhibitor (e.g., TAK-901), radioimmunotherapy (e.g.,actinium-225-labeled anti-CD33 antibody HuM195), Hedgehog inhibitor(e.g., PF-04449913), STAT3 inhibitor (e.g., OPB-31121), KB004, cancervaccine (e.g., AG858), bone marrow transplantation, stem celltransplantation, radiation therapy, and combinations thereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of chronic lymphocytic leukemia (CLL) includes,but is not limited to, a chemotherapeutic agent (e.g., fludarabine,cyclophosphamide, doxorubicin, vincristine, chlorambucil, bendamustine,chlorambucil, busulfan, gemcitabine, melphalan, pentostatin,mitoxantrone, 5-azacytidine, pemetrexed disodium), tyrosine kinaseinhibitor (e.g., EGFR inhibitor (e.g., erlotinib), BTK inhibitor (e.g.,PCI-32765), multikinase inhibitor (e.g., MGCD265, RGB-286638), CD-20targeting agent (e.g., rituximab, ofatumumab, RO5072759, LFB-R603), CD52targeting agent (e.g., alemtuzumab), prednisolone, darbepoetin alfa,lenalidomide, Bcl-2 inhibitor (e.g., ABT-263), immunotherapy (e.g.,allogeneic CD4+ memory Thl-like T cells/microparticle-boundanti-CD3/anti-CD28, autologous cytokine induced killer cells (CIK)),HDAC inhibitor (e.g., vorinostat, valproic acid, LBH589, JNJ-26481585,AR-42), XIAP inhibitor (e.g., AEG35156), CD-74 targeting agent (e.g.,milatuzumab), mTOR inhibitor (e.g., everolimus), AT-101, immunotoxin(e.g., CAT-8015, anti-Tac(Fv)-PE38 (LMB-2)), CD37 targeting agent (e.g.,TRU-016), radioimmunotherapy (e.g., 131-tositumomab),hydroxychloroquine, perifosine, SRC inhibitor (e.g., dasatinib),thalidomide, PI3K delta inhibitor (e.g., CAL-101), retinoid (e.g.,fenretinide), MDM2 antagonist (e.g., RO5045337), plerixafor, Aurorakinase inhibitor (e.g., MLN8237, TAK-901), proteasome inhibitor (e.g.,bortezomib), CD-19 targeting agent (e.g., MEDI-551, MOR208), MEKinhibitor (e.g., ABT-348), JAK-2 inhibitor (e.g., INCB018424),hypoxia-activated prodrug (e.g., TH-302), paclitaxel or a paclitaxelagent, HSP90 inhibitor, AKT inhibitor (e.g., MK2206), HMG-CoA inhibitor(e.g., simvastatin), GNKG186, radiation therapy, bone marrowtransplantation, stem cell transplantation, and a combination thereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules described herein, alone or in combinationwith another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1 oranti-TIM-3 antibody molecule), for treatment of acute lymphocyticleukemia (ALL) includes, but is not limited to, a chemotherapeutic agent(e.g., prednisolone, dexamethasone, vincristine, asparaginase,daunorubicin, cyclophosphamide, cytarabine, etoposide, thioguanine,mercaptopurine, clofarabine, liposomal annamycin, busulfan, etoposide,capecitabine, decitabine, azacitidine, topotecan, temozolomide),tyrosine kinase inhibitor (e.g., BCR/ABL inhibitor (e.g., imatinib,nilotinib), ON 01910.Na, multikinase inhibitor (e.g., sorafenib)), CD-20targeting agent (e.g., rituximab), CD52 targeting agent (e.g.,alemtuzumab), HSP90 inhibitor (e.g., STA-9090), mTOR inhibitor (e.g.,everolimus, rapamycin), JAK-2 inhibitor (e.g., INCB018424), HER2/neureceptor inhibitor (e.g., trastuzumab), proteasome inhibitor (e.g.,bortezomib), methotrexate, asparaginase, CD-22 targeting agent (e.g.,epratuzumab, inotuzumab), immunotherapy (e.g., autologous cytokineinduced killer cells (CIK), AHN-12), blinatumomab, cyclin-dependentkinase inhibitor (e.g., UCN-01), CD45 targeting agent (e.g., BC8), MDM2antagonist (e.g., RO5045337), immunotoxin (e.g., CAT-8015, DT2219ARL),HDAC inhibitor (e.g., JNJ-26481585), JVRS-100, paclitaxel or apaclitaxel agent, STAT3 inhibitor (e.g., OPB-31121), PARP inhibitor(e.g., veliparib), EZN-2285, radiation therapy, steroid, bone marrowtransplantation, stem cell transplantation, or a combination thereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules described herein, alone or in combinationwith another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1 oranti-TIM-3 antibody molecule), for treatment of acute myeloid leukemia(AML) includes, but is not limited to, a chemotherapeutic agent (e.g.,cytarabine, daunorubicin, idarubicin, clofarabine, decitabine,vosaroxin, azacitidine, clofarabine, ribavirin, CPX-351, treosulfan,elacytarabine, azacitidine), tyrosine kinase inhibitor (e.g., BCR/ABLinhibitor (e.g., imatinib, nilotinib), ON 01910.Na, multikinaseinhibitor (e.g., midostaurin, SU 11248, quizartinib, sorafinib)),immunotoxin (e.g., gemtuzumab ozogamicin), DT3881L3 fusion protein, HDACinhibitor (e.g., vorinostat, LBH589), plerixafor, mTOR inhibitor (e.g.,everolimus), SRC inhibitor (e.g., dasatinib), HSP90 inhbitor (e.g.,STA-9090), retinoid (e.g., bexarotene, Aurora kinase inhibitor (e.g., BI811283), JAK-2 inhibitor (e.g., INCB018424), Polo-like kinase inhibitor(e.g., BI 6727), cenersen, CD45 targeting agent (e.g., BC8),cyclin-dependent kinase inhibitor (e.g., UCN-01), MDM2 antagonist (e.g.,RO5045337), mTOR inhibitor (e.g., everolimus), LY573636-sodium, ZRx-101,MLN4924, lenalidomide, immunotherapy (e.g., AHN-12), histaminedihydrochloride, radiation therapy, bone marrow transplantation, stemcell transplantation, and a combination thereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules described herein, alone or in combinationwith another immunomodulator (e.g., an anti-LAG-3, anti-PD-L1 oranti-TIM-3 antibody molecule), for treatment of multiple myeloma (MM)includes, but is not limited to, a chemotherapeutic agent (e.g.,melphalan, amifostine, cyclophosphamide, doxorubicin, clofarabine,bendamustine, fludarabine, adriamycin, SyB L-0501), thalidomide,lenalidomide, dexamethasone, prednisone, pomalidomide, proteasomeinhibitor (e.g., bortezomib, carfilzomib, MLN9708), cancer vaccine(e.g., GVAX), CD-40 targeting agent (e.g., SGN-40, CHIR-12.12),perifosine, zoledronic acid, Immunotherapy (e.g., MAGE-A3, NY-ESO-1,HuMax-CD38), HDAC inhibitor (e.g., vorinostat, LBH589, AR-42), aplidin,cycline-dependent kinase inhibitor (e.g., PD-0332991, dinaciclib),arsenic trioxide, CB3304, HSP90 inhibitor (e.g., KW-2478), tyrosinekinase inhibitor (e.g., EGFR inhibitor (e.g., cetuximab), multikinaseinhibitor (e.g., AT9283)), VEGF inhibitor (e.g., bevacizumab),plerixafor, MEK inhibitor (e.g., AZD6244), IPH2101, atorvastatin,immunotoxin (e.g., BB-10901), NPI-0052, radioimmunotherapeutic (e.g.,yttrium Y 90 ibritumomab tiuxetan), STAT3 inhibitor (e.g., OPB-31121),MLN4924, Aurora kinase inhibitor (e.g., ENMD-2076), IMGN901, ACE-041,CK-2 inhibitor (e.g., CX-4945), radiation therapy, bone marrowtransplantation, stem cell transplantation, and a combination thereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of prostate cancer includes, but is not limitedto, a chemotherapeutic agent (e.g., docetaxel, carboplatin,fludarabine), abiraterone, hormonal therapy (e.g., flutamide,bicalutamide, nilutamide, cyproterone acetate, ketoconazole,aminoglutethimide, abarelix, degarelix, leuprolide, goserelin,triptorelin, buserelin), tyrosine kinase inhibitor (e.g., dual kinaseinhibitor (e.g., lapatanib), multikinase inhibitor (e.g., sorafenib,sunitinib)), VEGF inhibitor (e.g., bevacizumab), TAK-700, cancer vaccine(e.g., BPX-101, PEP223), lenalidomide, TOK-001, IGF-1 receptor inhibitor(e.g., cixutumumab), TRC105, Aurora A kinase inhibitor (e.g., MLN8237),proteasome inhibitor (e.g., bortezomib), OGX-011, radioimmunotherapy(e.g., HuJ591-GS), HDAC inhibitor (e.g., valproic acid, SB939, LBH589),hydroxychloroquine, mTOR inhibitor (e.g., everolimus), dovitiniblactate, diindolylmethane, efavirenz, OGX-427, genistein, IMC-3G3,bafetinib, CP-675,206, radiation therapy, surgery, or a combinationthereof.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of HNSCC includes, but is not limited to, oneor both of Compound A8 as described herein (or a compound described inPCT Publication No. WO2010/029082) and cetuximab (e.g., Erbitux,marketed by BMS). In some embodiments, the therapeutic (e.g., theCompound A8 or compound related to A8) is a PI3K modulator, e.g., a PI3Kinhibitor. In some embodiments, the therapeutic (e.g., cetuximab)modulates, e.g., inhibits, EGFR. In some embodiments, the cancer has, oris identified as having, elevated levels or activity of PI3K or EGFRcompared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of gastric cancer, e.g., MSI-high and/or EBV+gastric cancer, includes, but is not limited to, Compound A8 asdescribed herein (or a compound described in PCT Publication No.WO2010/029082). In some embodiments, the therapeutic (e.g., the CompoundA8 or compound related to A8) is a PI3K modulator, e.g., a PI3Kinhibitor. In some embodiments, the cancer has, or is identified ashaving, elevated levels or activity of PI3K compared to a control cellor reference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of gastric cancer, e.g., MSI-high and/orRNF43-inactivated gastric cancer, includes, but is not limited to,Compound A28 as described herein (or a compound described in PCTPublication No. WO2010/101849). In some embodiments, the therapeutic(e.g., the Compound A28 or compound related to A28) is a modulator,e.g., inhibitor, of porcupine. In some embodiments, the cancer has, oris identified as having, elevated levels or activity of porcupinecompared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of GI stromal tumor (GIST), includes, but isnot limited to, Compound A16 as described herein (or a compounddescribed in PCT Publication No. WO1999/003854). In some embodiments,the therapeutic (e.g., the Compound A16 or compound related to A16) is amodulator, e.g., inhibitor, of a tyrosine kinase. In some embodiments,the cancer has, or is determined to have, elevated levels or activity ofa tyrosine kinase compared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of NSCLC, e.g., squamous or adenocarcinoma,includes, but is not limited to, one or both of Compound A17 asdescribed herein (or a compound described in U.S. Pat. Nos. 7,767,675and 8,420,645) and Compound A23 as described herein (or a compounddescribed in PCT Publication No. WO2003/077914). In some embodiments,the compound (e.g., the Compound A17 or compound related to A17)modulates, e.g., inhibits, c-MET. In some embodiments, the compound(e.g., the Compound A23 or compound related to A23) modulates, e.g.,inhibits, Alk. In some embodiments, the cancer has, or is determined tohave, elevated levels or activity of one or both of c-MET or Alkcompared to a control cell or reference value. In some embodiments, thecancer has, or is identified as having, a mutation in EGFR.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of melanoma (e.g., NRAS melanoma) includes, butis not limited to, one or both of Compound A24 as described herein (or acompound described in U.S. Pat. Nos. 8,415,355 and 8,685,980) andCompound A34 as described herein (or a compound described in PCTPublication No. WO2003/077914). In some embodiments, the compound (e.g.,the Compound A24 or compound related to A24) modulates, e.g., inhibits,one or more of JAK and CDK4/6. In some embodiments, the compound (e.g.,the Compound A34 or compound related to A34) modulates, e.g., inhibits,MEK. In some embodiments, the cancer has, or is identified as having,elevated levels or activity of one or more of JAK, CDK4/6, and MEKcompared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of melanoma (e.g., NRAS melanoma) includes, butis not limited to, one or both of Compound A29 as described herein (or acompound described in PCT Publication No. WO2011/025927) and CompoundA34 as described herein (or a compound described in PCT Publication No.WO2003/077914). In some embodiments, the compound (e.g., the CompoundA29 or compound related to A29) modulates, e.g., inhibits, BRAF. In someembodiments, the compound (e.g., the Compound A34 or compound related toA34) modulates, e.g., inhibits, MEK. In some embodiments, the cancerhas, or is identified as having, elevated levels or activity of one orboth of BRAF and MEK compared to a control cell or reference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of squamous NSCLC includes, but is not limitedto, Compound A5 as described herein (or a compound described in U.S.Pat. No. 8,552,002). In some embodiments, the compound (e.g., theCompound A5 or compound related to A5) modulates, e.g., inhibits, FGFR.In some embodiments, the cancer has, or is identified as having,elevated levels or activity of FGFR compared to a control cell orreference value.

An example of suitable therapeutics for use in combination with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), for treatment of colorectal cancer includes, but is notlimited to, one or both of Compound A29 as described herein (or acompound PCT Publication No. WO2011/025927) and cetuximab (e.g.,Erbitux, marketed by BMS). In some embodiments, the therapeutic (e.g.,the Compound A29 or compound related to A29) modulates, e.g., inhibits,BRAF. In some embodiments, the therapeutic (e.g., cetuximab) modulates,e.g., inhibits EGFR. In some embodiments, the cancer has, or isidentified as having, elevated levels or activity of BRAF or EGFRcompared to a control cell or reference value.

This disclosure also provides a method of treating cancer with CompoundA8, cetuximab, and a PD-1 antibody molecule (optionally in combinationwith a TIM-3 antibody molecule or LAG-3 antibody molecule). In someembodiments, the patient is first treated with Compound A8 andcetuximab. This treatment continues for an amount of time, e.g., apredetermined amount of time, e.g., about 1, 2, 4, 6, 8, 10, or 12months. Next, the PD-1 antibody molecule (optionally in combination witha TIM-3 antibody molecule or LAG-3 antibody molecule) is administered.The PD-1 antibody can optionally be administered in combination withcetuximab.

In some embodiments, the patient is first treated with all three ofCompound A8, cetuximab, and a PD-1 antibody molecule (optionally incombination with a TIM-3 antibody molecule or LAG-3 antibody molecule).This treatment continues for an amount of time, e.g., a predeterminedamount of time, e.g., about 6, 8, 10, or 12 months. Next, the CompoundA8 and/or cetuximab can be tapered off, so that the maintenance phaseinvolves treatment with the PD-1 antibody molecule (e.g., as amonotherapy, or in combination with a TIM-3 antibody molecule or LAG-3antibody molecule) but not Compound A8 or cetuximab.

In other embodiments, the three compounds (Compound A8, cetuximab, and aPD-1 antibody molecule, optionally in combination with a TIM-3 antibodymolecule or LAG-3 antibody molecule) are given sequentially at theoutset of the treatment. For instance, Compound A8 and cetuximab can begiven first, as described above. Next, the PD-1 antibody molecule(optionally in combination with a TIM-3 antibody molecule or LAG-3antibody molecule) is added to the regimen. Next, the Compound A8 and/orcetuximab can be tapered off as described above.

Exemplary doses for the three (or more) agent regimens are as follows.The PD-1 antibody molecule can be administered, e.g., at a dose of about1 to 40 mg/kg, e.g., 1 to 30 mg/kg, e.g., about 5 to 25 mg/kg, about 10to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg. In some embodiments,the Compound A8 is administered at a dose of approximately 200-300,300-400, or 200-400 mg. In some embodiments, the cetuximab isadministered at a 400 mg/m2 initial dose as a 120-minute intravenousinfusion followed by 250 mg/m2 weekly infused over 60 minutes. Inembodiments, one or more of the Compound A8, cetuximab, and PD-1antibody molecule is administered at a dose that is lower than the doseat which that agent is typically administered as a monotherapy, e.g.,about 0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or80-90% lower than the dose at which that agent is typically administeredas a monotherapy. In embodiments, the one or more of the Compound A8,cetuximab, and PD-1 antibody molecule is administered at a dose that islower than the dose of that agent recited in this paragraph, e.g., about0-10%, 10-20%, 20-30%, 30-40%, 40-50%, 50-60%, 60-70%, 70-80%, or 80-90%lower than the dose of that agent recited in this paragraph. In certainembodiments, the concentration of the Compound A8 that is required toachieve inhibition, e.g., growth inhibition, is lower when the CompoundA8 is administered in combination with one or both of the cetuximab andPD-1 antibody molecule than when the Compound A8 is administeredindividually. In certain embodiments, the concentration of the cetuximabthat is required to achieve inhibition, e.g., growth inhibition, islower when the cetuximab is administered in combination with one or bothof the Compound A8 and PD-1 antibody molecule than when the cetuximab isadministered individually. In certain embodiments, the concentration ofthe PD-1 antibody molecule that is required to achieve inhibition, e.g.,growth inhibition, is lower when the PD-1 antibody molecule isadministered in combination with one or both of the cetuximab andCompound A8 than when the PD-1 antibody molecule is administeredindividually.

Additionally disclosed herein is a method of treating cancer with theanti-PD-1 antibody molecules, alone or in combination with anotherimmunomodulator (e.g., an anti-LAG-3, anti-PD-L1 or anti-TIM-3 antibodymolecule), and a targeted anti-cancer agent, e.g., an agent that targetsone or more proteins. In some embodiments, the anti-PD-1 antibodymolecule (and optionally other immunomodulator(s)) are administeredfirst, and the targeted anti-cancer agent is administered second. Thelength of time between administration of the anti-PD-1 antibody moleculeand the targeted anti-cancer agent can be, e.g., 10, 20, or 30 minutes,1, 2, 4, 6, or 12 hours, or 1, 2, 3, 4, 5, 6, or 7 days, or any span oftime within this range. In certain embodiments, the anti-PD-1 antibodymolecule is administered repeatedly over a period of time (e.g., 1, 2,3, 4, 5, or 6 days, or 1, 2, 4, 8, 12, 16, or 20 weeks, or any span oftime within this range) before the targeted anti-cancer agent isadministered. In other embodiments, the anti-PD-1 antibody molecule andthe targeted anti-cancer agent are administered at substantially thesame time.

Infectious Diseases

Other methods of the invention are used to treat patients that have beenexposed to particular toxins or pathogens. Accordingly, another aspectof the invention provides a method of treating an infectious disease ina subject comprising administering to the subject an anti-PD-1 antibodymolecule, such that the subject is treated for the infectious disease.

In the treatment of infection (e.g., acute and/or chronic),administration of the anti-PD-1 antibody molecules can be combined withconventional treatments in addition to or in lieu of stimulating naturalhost immune defenses to infection. Natural host immune defenses toinfection include, but are not limited to inflammation, fever,antibody-mediated host defense, T-lymphocyte-mediated host defenses,including lymphokine secretion and cytotoxic T-cells (especially duringviral infection), complement mediated lysis and opsonization(facilitated phagocytosis), and phagocytosis. The ability of theanti-PD-1 antibody molecules to reactivate dysfunctional T-cells wouldbe useful to treat chronic infections, in particular those in whichcell-mediated immunity is important for complete recovery.

Similar to its application to tumors as discussed above, antibodymediated PD-1 blockade can be used alone, or as an adjuvant, incombination with vaccines, to stimulate the immune response topathogens, toxins, and self-antigens. Examples of pathogens for whichthis therapeutic approach may be particularly useful, include pathogensfor which there is currently no effective vaccine, or pathogens forwhich conventional vaccines are less than completely effective. Theseinclude, but are not limited to HIV, Hepatitis (A, B, & C), Influenza,Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, PseudomonasAeruginosa. PD-1 blockade is particularly useful against establishedinfections by agents such as HIV that present altered antigens over thecourse of the infections. These novel epitopes are recognized as foreignat the time of anti-human PD-1 administration, thus provoking a strong Tcell response that is not dampened by negative signals through PD-1.

Viruses

For infections resulting from viral causes, the anti-PD-1 antibodymolecules can be combined by application simultaneous with, prior to orsubsequent to application of standard therapies for treating viralinfections. Such standard therapies vary depending upon type of virus,although in almost all cases, administration of human serum containingantibodies (e.g., IgA, IgG) specific to the virus can be effective.

Some examples of pathogenic viruses causing infections treatable bymethods include HIV, hepatitis (A, B, or C), herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus,influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus,cornovirus, respiratory syncytial virus, mumps virus, rotavirus, measlesvirus, rubella virus, parvovirus, vaccinia virus, HTLV virus, denguevirus, papillomavirus, molluscum virus, poliovirus, rabies virus, JCvirus and arboviral encephalitis virus.

In one embodiment, the infection is an influenza infection. Influenzainfection can result in fever, cough, myalgia, headache and malaise,which often occur in seasonal epidemics. Influenza is also associatedwith a number of postinfectious disorders, such as encephalitis,myopericarditis, Goodpasture's syndrome, and Reye's syndrome. Influenzainfection also suppresses normal pulmonary antibacterial defenses, suchthat patient's recovering from influenza have an increased risk ofdeveloping bacterial pneumonia. Influenza viral surface proteins showmarked antigenic variation, resulting from mutation and recombination.Thus, cytolytic T lymphocytes are the host's primary vehicle for theelimination of virus after infection. Influenza is classified into threeprimary types: A, B and C. Influenza A is unique in that it infects bothhumans and many other animals (e.g., pigs, horses, birds and seals) andis the principal cause of pandemic influenza. Also, when a cell isinfected by two different influenza A strains, the segmented RNA genomesof two parental virus types mix during replication to create a hybridreplicant, resulting in new epidemic strains. Influenza B does notreplicate in animals and thus has less genetic variation and influenza Chas only a single serotype.

Most conventional therapies are palliatives of the symptoms resultingfrom infection, while the host's immune response actually clears thedisease. However, certain strains (e.g., influenza A) can cause moreserious illness and death. Influenza A may be treated both clinicallyand prophylactically by the administration of the cyclic aminesinhibitors amantadine and rimantadine, which inhibit viral replication.However, the clinical utility of these drugs is limited due to therelatively high incidence of adverse reactions, their narrow anti-viralspectrum (influenza A only), and the propensity of the virus to becomeresistant. The administration of serum IgG antibody to the majorinfluenza surface proteins, hemagglutinin and neuraminidase can preventpulmonary infection, whereas mucosal IgA is required to preventinfection of the upper respiratory tract and trachea. The most effectivecurrent treatment for influenza is vaccination with the administrationof virus inactivated with formalin or β-propiolactone.

In another embodiment, the infection is a hepatitis infection, e.g., aHepatitis B or C infection.

Hepatitis B virus (HB-V) is the most infectious known bloodbornepathogen. It is a major cause of acute and chronic heptatis and hepaticcarcinoma, as well as life-long, chronic infection. Following infection,the virus replicates in hepatocytes, which also then shed the surfaceantigen HBsAg. The detection of excessive levels of HBsAg in serum isused a standard method for diagnosing a hepatitis B infection. An acuteinfection may resolve or it can develop into a chronic persistentinfection. Current treatments for chronic HBV include α-interferon,which increases the expression of class I human leukocyte antigen (HLA)on the surface of hepatocytes, thereby facilitating their recognition bycytotoxic T lymphocytes. Additionally, the nucleoside analogsganciclovir, famciclovir and lamivudine have also shown some efficacy inthe treatment of HBV infection in clinical trials. Additional treatmentsfor HBV include pegylated a-interferon, adenfovir, entecavir andtelbivudine. While passive immunity can be conferred through parentaladministration of anti-HBsAg serum antibodies, vaccination withinactivated or recombinant HBsAg also confers resistance to infection.The anti-PD-1 antibody molecules may be combined with conventionaltreatments for hepatitis B infections for therapeutic advantage.

Hepatitis C virus (HC-V) infection may lead to a chronic form ofhepatitis, resulting in cirrosis. While symptoms are similar toinfections resulting from Hepatitis B, in distinct contrast to HB-V,infected hosts can be asymptomatic for 10-20 years. The anti-PD-1antibody molecule can be administered as a monotherapy, or combined withthe standard of care for hepatitis C infection. For example, theanti-PD-1 antibody molecule can be administered with one or more ofSovaldi (sofosbuvir) Olysio (simeprevir), plus ribavirin or pegylatedinterferon. Although regimens that include Incivek (telaprevir) orVictrelis (boceprevir) plus ribavirin and pegylated interferon are alsoapproved, they are associated with increased side effects and longerduration of treatment and are therefore not considered preferredregimens.

Conventional treatment for HC-V infection includes the administration ofa combination of α-interferon and ribavirin. A promising potentialtherapy for HC-V infection is the protease inhibitor telaprevir(VX-960). Additional treatments include: anti-PD-1 antibody (MDX-1106,Medarex), bavituximab (an antibody that binds anionic phospholipidphosphatidylserine in a B2-glycoprotein I dependent manner, PeregrinePharmaceuticals), anti-HPV viral coat protein E2 antibod(y)(ies) (e.g.,ATL 6865−Ab68+Ab65, XTL Pharmaceuticals) and Civacir® (polyclonalanti-HCV human immune globulin). The anti-PD-L1 antibodies of theinvention may be combined with one or more of these treatments forhepatitis C infections for therapeutic advantage. Protease, polymeraseand NSSA inhibitors which may be used in combination with the anti-PD-1antibody molecules to specifically treat Hepatitis C infection includethose described in US 2013/0045202, incorporated herein by reference.

In another embodiment, the infection is a measles virus. After anincubation of 9-11 days, hosts infected with the measles virus developfever, cough, coryza and conjunctivitis. Within 1-2 days, anerythematous, maculopapular rash develop, which quickly spreads over theentire body. Because infection also suppresses cellular immunity, thehost is at greater risk for developing bacterial superinfections,including otitis media, pneumonia and postinfectious encephalomyelitis.Acute infection is associated with significant morbidity and mortality,especially in malnourished adolescents.

Treatment for measles includes the passive administration of pooledhuman IgG, which can prevent infection in non-immune subjects, even ifgiven up to one week after exposure. However, prior immunization withlive, attenuated virus is the most effective treatment and preventsdisease in more than 95% of those immunized. As there is one serotype ofthis virus, a single immunization or infection typically results inprotection for life from subsequent infection.

In a small proportion of infected hosts, measles can develop into SSPE,which is a chronic progressive neurologic disorder resulting from apersistent infection of the central nervous system. SSPE is caused byclonal variants of measles virus with defects that interfere with virionassembly and budding. For these patients, reactivation of T-cells withthe anti-PD-1 antibody molecules so as to facilitate viral clearancewould be desirable.

In another embodiment, the infection is HIV. HIV attacks CD4⁺ cells,including T-lymphocytes, monocyte-macrophages, follicular dendriticcells and Langerhan's cells, and CD4⁺ helper/inducer cells are depleted.As a result, the host acquires a severe defect in cell-mediatedimmunity. Infection with HIV results in AIDS in at least 50% ofindividuals, and is transmitted via sexual contact, administration ofinfected blood or blood products, artificial insemination with infectedsemen, exposure to blood-containing needles or syringes and transmissionfrom an infected mother to infant during childbirth.

A host infected with HIV may be asymptomatic, or may develop an acuteillness that resembling mononucleosis—fever, headache, sore throat,malaise and rash. Symptoms can progress to progressive immunedysfunction, including persistent fever, night sweats, weight loss,unexplained diarrhea, eczema, psoriasis, seborrheic dermatitis, herpeszoster, oral candidiasis and oral hairy leukoplakia. Opportunisticinfections by a host of parasites are common in patients whoseinfections develop into AIDS.

Treatments for HIV include antiviral therapies including nucleosideanalogs, zidovudine (AST) either alone or in combination with didanosineor zalcitabine, dideoxyinosine, dideoxycytidine, lamidvudine, stavudine;reverse transcriptive inhibitors such as delavirdine, nevirapine,loviride, and proteinase inhibitors such as saquinavir, ritonavir,indinavir and nelfinavir. The anti-PD-1 antibody molecules may becombined with conventional treatments for HIV infections for therapeuticadvantage.

In another embodiment, the infection is a Cytomegalovirus (CMV). CMVinfection is often associated with persistent, latent and recurrentinfection. CMV infects and remains latent in monocytes andgranulocyte-monocyte progenitor cells. The clinical symptoms of CMVinclude mononucleosis-like symptoms (i.e., fever, swollen glands,malaise), and a tendancy to develop allergic skin rashes to antibiotics.The virus is spread by direct contact. The virus is shed in the urine,saliva, semen and to a lesser extent in other body fluids. Transmissioncan also occur from an infected mother to her fetus or newborn and byblood transfusion and organ transplants. CMV infection results ingeneral impairment of cellular immunity, characterized by impairedblastogenic responses to nonspecific mitogens and specific CMV antigens,diminished cytotoxic ability and elevation of CD8 lymphocyte number ofCD4⁺ lymphocytes.

Treatments of CMV infection include the anti-virals ganciclovir,foscarnet and cidovir, but these druges are typically only prescribed inimmunocompromised patients. The anti-PD-1 antibody molecules may becombined with conventional treatments for cytomegalovirus infections fortherapeutic advantage.

In another embodiment, the infection is Epstein-Barr virus (EBV). EBVcan establish persistent and latent infections and primarily attacks Bcells. Infection with EBV results in the clinical condition ofinfectious mononucleosis, which includes fever, sore throat, often withexudate, generalized lymphadenopathy and splenomegaly. Hepatitis is alsopresent, which can develop into jaundice.

While typical treatments for EBV infections are palliative of symptoms,EBV is associated with the development of certain cancers such asBurkitt's lymphoma and nasopharyngeal cancer. Thus, clearance of viralinfection before these complications result would be of great benefit.The anti-PD-1 antibody molecules may be combined with conventionaltreatments for Epstein-Barr virus infections for therapeutic advantage.

In another embodiment, the infection is Herpes simplex virus (HSV). HSVis transmitted by direct contact with an infected host. A directinfection may be asymptomatic, but typically result in blisterscontaining infectious particles. The disease manifests as cycles ofactive periods of disease, in which lesions appear and disappear as theviral latently infect the nerve ganglion for subsequent outbreaks.Lesions may be on the face, genitals, eyes and/or hands. In some case,an infection can also cause encephalitis.

Treatments for herpes infections are directed primarily to resolving thesymptomatic outbreaks, and include systemic antiviral medicines such as:acyclovir (e.g., Zovirax®), valaciclovir, famciclovir, penciclovir, andtopical medications such as docosanol (Abreva®), tromantadine andzilactin. The clearance of latent infections of herpes would be of greatclinical benefit. The anti-PD-1 antibody molecules may be combined withconventional treatments for herpes virus infections for therapeuticadvantage.

In another embodiment, the infection is Human T-lymphotrophic virus(HTLV-1, HTLV-2). HTLV is transmitted via sexual contact, breast feedingor exposure to contaminated blood. The virus activates a subset of T_(H)cells called Thl cells, resulting in their overproliferation andoverproduction of Thl related cytokines (e.g., IFN-γ and TNF-α). This inturn results in a suppression of Th2 lymphocytes and reduction of Th2cytokine production (e.g., IL-4, IL-5, IL-10 and IL-13), causing areduction in the ability of an infected host to mount an adequate immuneresponse to invading organisms requiring a Th2-dependent response forclearance (e.g., parasitic infections, production of mucosal and humoralantibodies).

HTLV infections cause lead to opportunistic infections resulting inbronchiectasis, dermatitis and superinfections with Staphylococcus spp.and Strongyloides spp. resulting in death from polymicrobial sepsis.HTLV infection can also lead directly to adult T-cell leukemia/lymphomaand progressive demyelinating upper motor neuron disease known asHAM/TSP. The clearance of HTLV latent infections would be of greatclinical benefit. The anti-PD-1 antibody molecules may be combined withconventional treatments for HTLV infections for therapeutic advantage.

In another embodiment, the infection is Human papilloma virus (HPV). HPVprimarily affects keratinocytes and occurs in two forms: cutaneous andgenital. Transmission is believed to occur through direct contact and/orsexual activity. Both cutaneous and genital HPV infection, can result inwarts and latent infections and sometimes recurring infections, whichare controlled by host immunity which controls the symptoms and blocksthe appearance of warts, but leaves the host capable of transmitting theinfection to others.

Infection with HPV can also lead to certain cancers, such as cervical,anal, vulvar, penile and oropharynial cancer. There are no known curesfor HPV infection, but current treatment is topical application ofImiquimod, which stimulates the immune system to attack the affectedarea. The clearance of HPV latent infections would be of great clinicalbenefit. The anti-PD-L1 antibodies of the invention may be combined withconventional treatments for HPV infections for therapeutic advantage.

Bacterial Infections

Some examples of pathogenic bacteria causing infections treatable bymethods of the invention include syphilis, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lymes disease bacteria. Theanti-PD-1 antibody molecules can be used in combination with existingtreatment modalities for the aforesaid infections. For example,Treatments for syphilis include penicillin (e.g., penicillin G.),tetracycline, doxycycline, ceftriaxone and azithromycin.

Lyme disease, caused by Borrelia burgdorferi is transmitted into humansthrough tick bites. The disease manifests initially as a localized rash,followed by flu-like symptoms including malaise, fever, headache, stiffneck and arthralgias. Later manifestations can include migratory andpolyarticular arthritis, neurologic and cardiac involvement with cranialnerve palsies and radiculopathy, myocarditis and arrhythmias. Some casesof Lyme disease become persistent, resulting in irreversible damageanalogous to tertiary syphilis. Current therapy for Lyme diseaseincludes primarily the administration of antibiotics.Antibiotic-resistant strains may be treated with hydroxychloroquine ormethotrexate. Antibiotic refractory patients with neuropathic pain canbe treated with gabapentin. Minocycline may be helpful in late/chronicLyme disease with neurological or other inflammatory manifestations.

Other forms of borreliois, such as those resulting from B. recurentis,B. hermsii, B. turicatae, B. parikeri., B. hispanica, B. duttonii and B.persica, as well leptospirosis (E.g., L. interrogans), typically resolvespontaneously unless blood titers reach concentrations to causeintrahepatic obstruction.

Fungi and Parasites

Some examples of pathogenic fungi causing infections treatable bymethods of the invention include Candida (albicans, krusei, glabrata,tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus,niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrixschenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis,Coccidioides immitis and Histoplasma capsulatum.

Some examples of pathogenic parasites causing infections treatable bymethods described herein include Entamoeba histolytica, Balantidiumcoli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

Additional Combination Therapies

Combinations of PD-1 antibody molecules with one or more secondtherapeutics are provided herein. Many of the combinations in thissection are useful in treating cancer, but other indications are alsodescribed. This section focuses on combinations of anti-PD-1 antibodymolecules, optionally in combination with one or more immunomodulators(e.g., an anti-TIM-3 antibody molecule, an anti-LAG-3 antibody molecule,or an anti-PD-L1 antibody molecule), with one or more of the agentsdescribed in Table 7. In the combinations herein below, in oneembodiment, the anti-PD-1 antibody molecule includes:

(a) a heavy chain variable region (VH) comprising a VHCDR1 amino acidsequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5,and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a light chainvariable region (VL) comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 33;

(b) a VH comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO:1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32;

(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, aVHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO:14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or

(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; aVHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acidsequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

In the combinations herein below, in another embodiment, the anti-PD-1antibody molecule comprises (i) a heavy chain variable region (VH)comprising a VHCDR1 amino acid sequence chosen from SEQ ID NO: 1, SEQ IDNO: 4, or SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2or SEQ ID NO: 5; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and(ii) a light chain variable region (VL) comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10 or SEQ ID NO: 13, a VLCDR2 amino acid sequenceof SEQ ID NO: 11 or SEQ ID NO: 14, and a VLCDR3 amino acid sequence ofSEQ ID NO: 32 or SEQ ID NO: 33.

In one embodiment, the anti-PD-1 antibody molecule, e.g., an anti-PD-1antibody molecule as described herein, alone or in combination with oneor more other immunomodulators, is used in combination with a PKCinhibitor, Sotrastaurin (Compound A1), or a compound disclosed in PCTPublication No. WO 2005/039549, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the PKC inhibitor is Sotrastaurin(Compound A1) or a compound disclosed in PCT Publication No. WO2005/039549. In one embodiment, a PD-1 antibody molecule is used incombination with Sotrastaurin (Compound A1), or a compound as describedin PCT Publication No. WO 2005/039549, to treat a disorder such as acancer, a melanoma, a non-Hodgkin lymphoma, an inflammatory boweldisease, transplant rejection, an ophthalmic disorder, or psoriasis.

In certain embodiments, Sotrastaurin (Compound A1) is administered at adose of about 20 to 600 mg, e.g., about 200 to about 600 mg, about 50 mgto about 450 mg, about 100 mg to 400 mg, about 150 mg to 350 mg, orabout 200 mg to 300 mg, e.g., about 50 mg, 100 mg, 150 mg, 200 mg, 300mg, 400 mg, 500 mg, or 600 mg. The dosing schedule can vary from e.g.,every other day to daily, twice or three times a day.

In one embodiment, the anti-PD-1 antibody molecule, e.g., an anti-PD-1antibody molecule as described herein, alone or in combination with oneor more other immunomodulators, is used in combination with a BCR-ABLinhibitor, TASIGNA (Compound A2), or a compound disclosed in PCTPublication No. WO 2004/005281, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the BCR-ABL inhibitor is TASIGNA,or a compound disclosed in PCT Publication No. WO 2004/005281. In oneembodiment, a PD-1 antibody molecule is used in combination with TASIGNA(Compound A2), or a compound as described in PCT Publication No. WO2004/005281, to treat a disorder such as a lymphocytic leukemia,Parkinson's Disease, a neurologic cancer, a melanoma, adigestive/gastrointestinal cancer, a colorectal cancer, a myeloidleukemia, a head and neck cancer, or pulmonary hypertension.

In one embodiment, the BCR-ABL inhibitor or TASIGNA is administered at adose of about 300 mg (e.g., twice daily, e.g., for newly diagnosed Ph+CML-CP), or about 400 mg, e.g., twice daily, e.g., for resistant orintolerant Ph+ CML-CP and CML-AP). BCR-ABL inhibitor or a Compound A2 isadministered at a dose of about 300-400 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anHSP90 inhibitor, such as5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(Compound A3), or a compound disclosed in PCT Publication No. WO2010/060937 or WO 2004/072051, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the HSP90 inhibitor is5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(Compound A3), or a compound disclosed in PCT Publication No. WO2010/060937 or WO 2004/072051. In one embodiment, a PD-1 antibodymolecule is used in combination with5-(2,4-dihydroxy-5-isopropylphenyl)-N-ethyl-4-(4-(morpholinomethyl)phenyl)isoxazole-3-carboxamide(Compound A3), or a compound as described in PCT Publication No. WO2010/060937 or WO 2004/072051, to treat a disorder such as a cancer, amultiple myeloma, a non-small cell lung cancer, a lymphoma, a gastriccancer, a breast cancer, a digestive/gastrointestinal cancer, apancreatic cancer, a colorectal cancer, a solid tumor, or ahematopoiesis disorder.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aninhibitor of PI3K and/or mTOR, Dactolisib (Compound A4) or8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one(Compound A41), or a compound disclosed in PCT Publication No. WO2006/122806, to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PI3K and/or mTOR inhibitor is Dactolisib (CompoundA4),8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one(Compound A41), or a compound disclosed in PCT Publication No. WO2006/122806. In one embodiment, a PD-1 antibody molecule is used incombination with Dactolisib (Compound A4),8-(6-Methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one(Compound A41), or a compound described in PCT Publication No. WO2006/122806, to treat a disorder such as a cancer, a prostate cancer, aleukemia (e.g., lymphocytic leukemia), a breast cancer, a brain cancer,a bladder cancer, a pancreatic cancer, a renal cancer, a solid tumor, ora liver cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anFGFR inhibitor,3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea(Compound A5) or a compound disclosed in U.S. Pat. No. 8,552,002, totreat a disorder, e.g., a disorder described herein. In one embodiment,the FGFR inhibitor is3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea(Compound A5) or a compound disclosed in U.S. Pat. No. 8,552,002. In oneembodiment, a PD-1 antibody molecule is used in combination withCompound A5, or a compound as described in U.S. Pat. No. 8,552,002, totreat a disorder such as a digestive/gastrointestinal cancer, ahematological cancer, or a solid tumor.

In one embodiment, the FGFR inhibitor or3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-(6-((4-(4-ethylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1-methylurea(Compound A5) is administered at a dose of about 100-125 mg (e.g., perday), e.g., about 100 mg or about 125 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aPI3K inhibitor, Buparlisib (Compound A6), or a compound disclosed in PCTPublication No. WO 2007/084786, to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the PI3K inhibitor is Buparlisib(Compound A6) or a compound disclosed in PCT Publication No. WO2007/084786. In one embodiment, a PD-1 antibody molecule is used incombination with Buparlisib (Compound A6), or a compound disclosed inPCT Publication No. WO 2007/084786, to treat a disorder such as, aprostate cancer, a non-small cell lung cancer, an endocrine cancer, aleukemia, an ovarian cancer, a melanoma, a bladder cancer, a breastcancer, a female reproductive system cancer, adigestive/gastrointestinal cancer, a colorectal cancer, a glioblastomamultiforme, a solid tumor, a non-Hodgkin lymphoma, a hematopoiesisdisorder, or a head and neck cancer.

In one embodiment, the PI3K inhibitor or Buparlisib (Compound A6) isadministered at a dose of about 100 mg (e.g., per day).

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anFGFR inhibitor,8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7) or a compound disclosed in PCT Publication No. WO2009/141386 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the FGFR inhibitor is8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7) or a compound disclosed in a PCT Publication No. WO2009/141386. In one embodiment, the FGFR inhibitor is8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7). In one embodiment, a PD-1 antibody molecule is used incombination with8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7), or a compound disclosed in PCT Publication No. WO2009/141386, to treat a disorder such as a cancer characterized byangiogenesis.

In one embodiment, the FGFR inhibitor or8-(2,6-difluoro-3,5-dimethoxyphenyl)-N-(4-((dimethylamino)methyl)-1H-imidazol-2-yl)quinoxaline-5-carboxamide(Compound A7) is administered at a dose of e.g., from approximately 3 mgto approximately 5 g, more preferably from approximately 10 mg toapproximately 1.5 g per person per day, optionally divided into 1 to 3single doses which may, for example, be of the same size.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aPI3K inhibitor,(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8) or a compound disclosed PCT Publication No. WO 2010/029082to treat a disorder, e.g., a disorder described herein. In oneembodiment, the PI3K inhibitor is(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8) or a compound disclosed PCT Publication No. WO2010/029082. In one embodiment, a PD-1 antibody molecule is used incombination with(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8), or a compound disclosed PCT Publication No. WO2010/029082, to treat a disorder such as a gastric cancer, a breastcancer, a pancreatic cancer, a digestive/gastrointestinal cancer, asolid tumor, and a head and neck cancer.

In one embodiment, the PI3K inhibitor or(S)—N1-(4-methyl-5-(2-(1,1,1-trifluoro-2-methylpropan-2-yl)pyridin-4-yl)thiazol-2-yl)pyrrolidine-1,2-dicarboxamide(Compound A8) is administered at a dose of about 150-300, 200-300,200-400, or 300-400 mg (e.g., per day), e.g., about 200, 300, or 400 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aninhibitor of cytochrome P450 (e.g., a CYP17 inhibitor) or a compounddisclosed in PCT Publication No. WO 2010/149755, to treat a disorder,e.g., a disorder described herein. In one embodiment, the cytochromeP450 inhibitor (e.g., the CYP17 inhibitor) is a compound disclosed inPCT Publication No. WO 2010/149755. In one embodiment, a PD-1 antibodymolecule is used in combination with a compound disclosed in PCTPublication No. WO 2010/149755, to treat prostate cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anHDM2 inhibitor,(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10) or a compound disclosed in PCT Publication No. WO2011/076786 to treat a disorder, e.g., a disorder described herein). Inone embodiment, the HDM2 inhibitor is(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10) or a compound disclosed in PCT Publication No. WO2011/076786. In one embodiment, a PD-1 antibody molecule is used incombination with(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10), or a compound disclosed in PCTPublication No. WO2011/076786, to treat a disorder such as a solid tumor.

In one embodiment, the HDM2 inhibitor or(S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one(Compound A10) is administered at a dose of about 400 to 700 mg, e.g.,administered three times weekly, 2 weeks on and one week off. In someembodiments, the dose is about 400, 500, 600, or 700 mg; about 400-500,500-600, or 600-700 mg, e.g., administered three times weekly.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aniron chelating agent, Deferasirox (also known as EXJADE; Compound A1l),or a compound disclosed in PCT Publication No. WO 1997/049395 to treat adisorder, e.g., a disorder described herein. In one embodiment, the ironchelating agent is Deferasirox or a compound disclosed in PCTPublication No. WO 1997/049395. In one embodiment, the iron chelatingagent is Deferasirox (Compound A11). In one embodiment, a PD-1 antibodymolecule is used in combination with Deferasirox (Compound A11), or acompound disclosed in PCT Publication No. WO 1997/049395, to treat ironoverload, hemochromatosis, or myelodysplasia.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anaromatase inhibitor, Letrozole (also known as FEMARA; Compound A12), ora compound disclosed in U.S. Pat. No. 4,978,672 to treat a disorder,e.g., a disorder described herein. In one embodiment, the aromataseinhibitor is Letrozole (Compound A12) or a compound disclosed in U.S.Pat. No. 4,978,672. In one embodiment, a PD-1 antibody molecule is usedin combination with Letrozole (Compound A12), or a compound disclosed inU.S. Pat. No. 4,978,672, to treat a disorder such as a cancer, aleiomyosarcoma, an endometrium cancer, a breast cancer, a femalereproductive system cancer, or a hormone deficiency.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aPI3K inhibitor, e.g., a pan-PI3K inhibitor,(4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(Compound A13) or a compound disclosed in PCT Publication No.WO2013/124826 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PI3K inhibitor is(4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(Compound A13) or a compound disclosed in PCT Publication No.WO2013/124826. In one embodiment, a PD-1 antibody molecule is used incombination with(4S,5R)-3-(2′-amino-2-morpholino-4′-(trifluoromethyl)-[4,5′-bipyrimidin]-6-yl)-4-(hydroxymethyl)-5-methyloxazolidin-2-one(Compound A13), or a compound disclosed in PCT Publication No.WO2013/124826, to treat a disorder such as a cancer or an advanced solidtumor.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aninhibitor of p53 and/or a p53/Mdm2 interaction,(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Compound A14), or a compound disclosed in PCT Publication No.WO2013/111105 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the p53 and/or a p53/Mdm2 interaction inhibitor is(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Compound A14) or a compound disclosed in PCT Publication No.WO2013/111105. In one embodiment, a PD-1 antibody molecule is used incombination with(S)-5-(5-chloro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-6-(4-chlorophenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-1-isopropyl-5,6-dihydropyrrolo[3,4-d]imidazol-4(1H)-one(Compound A14), or a compound disclosed in PCT Publication No.WO2013/111105, to treat a disorder such as a cancer or a soft tissuesarcoma.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aCSF-1R tyrosine kinase inhibitor,4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A15), or a compound disclosed in PCT Publication No. WO2005/073224 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the CSF-1R tyrosine kinase inhibitor is4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A15) or a compound disclosed in PCT Publication No. WO2005/073224. In one embodiment, a PD-1 antibody molecule is used incombination with4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide(Compound A15) or a compound disclosed in PCT Publication No. WO2005/073224, to treat a disorder such as cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anapoptosis inducer and/or an angiogenesis inhibitor, such as Imatinibmesylate (also known as GLEEVEC; Compound A16) or a compound disclosedin PCT Publication No. WO1999/003854 to treat a disorder, e.g., adisorder described. In one embodiment, the apoptosis inducer and/or anangiogenesis inhibitor is Imatinib mesylate (Compound A16) or a compounddisclosed in PCT Publication No. WO1999/003854. In one embodiment, aPD-1 antibody molecule is used in combination with Imatinib mesylate(Compound A16), or a compound disclosed in PCT Publication No.WO1999/003854, to treat a disorder such as a cancer, a multiple myeloma,a prostate cancer, a non-small cell lung cancer, a lymphoma, a gastriccancer, a melanoma, a breast cancer, a pancreatic cancer, adigestive/gastrointestinal cancer, a colorectal cancer, a glioblastomamultiforme, a liver cancer, a head and neck cancer, asthma, multiplesclerosis, allergy, Alzheimer's dementia, amyotrophic lateral sclerosis,or rheumatoid arthritis.

In certain embodiments, Imatinib mesylate (Compound A16) is administeredat a dose of about 100 to 1000 mg, e.g., about 200 mg to 800 mg, about300 mg to 700 mg, or about 400 mg to 600 mg, e.g., about 200 mg, 300 mg,400 mg, 500 mg, 600 mg, or 700 mg. The dosing schedule can vary frome.g., every other day to daily, twice or three times a day. In oneembodiment, Imatinib mesylate is administered at an oral dose from about100 mg to 600 mg daily, e.g., about 100 mg, 200 mg, 260 mg, 300 mg, 400mg, or 600 mg daily.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aJAK inhibitor,2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof, or a compounddisclosed in PCT Publication No. WO 2007/070514, to treat a disorder,e.g., a disorder described herein. In one embodiment, the JAK inhibitoris2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof, or a compounddisclosed in PCT Publication No. WO 2007/070514. In one embodiment, aPD-1 antibody molecule is used in combination with2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof, or a compounddisclosed in PCT Publication No. WO 2007/070514, to treat a disordersuch as colorectal cancer, myeloid leukemia, hematological cancer,autoimmune disease, non-Hodgkin lymphoma, or thrombocythemia.

In one embodiment, the JAK inhibitor or a2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl)benzamide(Compound A17), or a dihydrochloric salt thereof is administered at adose of about 400-600 mg (e.g., per day), e.g., about 400, 500, or 600mg, or about 400-500 or 500-600 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aJAK inhibitor, Ruxolitinib Phosphate (also known as JAKAFI; CompoundA18) or a compound disclosed in PCT Publication No. WO 2007/070514 totreat a disorder, e.g., a disorder described herein. In one embodiment,the JAK inhibitor is Ruxolitinib Phosphate (Compound A18) or a compounddisclosed in PCT Publication No. WO 2007/070514. In one embodiment, aPD-1 antibody molecule is used in combination with Ruxolitinib Phosphate(Compound A18), or a compound disclosed in PCT Publication No. WO2007/070514, to treat a disorder such as a prostate cancer, alymphocytic leukemia, a multiple myeloma, a lymphoma, a lung cancer, aleukemia, cachexia, a breast cancer, a pancreatic cancer, rheumatoidarthritis, psoriasis, a colorectal cancer, a myeloid leukemia, ahematological cancer, an autoimmune disease, a non-Hodgkin lymphoma, orthrombocythemia.

In one embodiment, the JAK inhibitor or Ruxolitinib Phosphate (CompoundA18) is administered at a dose of about 15-25 mg, e.g., twice daily. Insome embodiments, the dose is about 15, 20, or 25 mg, or about 15-20 or20-25 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with adeacetylase (DAC) inhibitor, Panobinostat (Compound A19), or a compounddisclosed in PCT Publication No. WO 2014/072493 to treat a disorder,e.g., a disorder described herein. In one embodiment, the DAC inhibitoris Panobinostat (Compound A19) or a compound disclosed in PCTPublication No. WO 2014/072493. In one embodiment, a PD-1 antibodymolecule is used in combination with Panobinostat (Compound A19), acompound disclosed in PCT Publication No. WO 2014/072493, to treat adisorder such as a small cell lung cancer, a respiratory/thoraciccancer, a prostate cancer, a multiple myeloma, myelodysplastic syndrome,a bone cancer, a non-small cell lung cancer, an endocrine cancer, alymphoma, a neurologic cancer, a leukemia, HIV/AIDS, an immune disorder,transplant rejection, a gastric cancer, a melanoma, a breast cancer, apancreatic cancer, a colorectal cancer, a glioblastoma multiforme, amyeloid leukemia, a hematological cancer, a renal cancer, a non-Hodgkinlymphoma, a head and neck cancer, a hematopoiesis disorders, or a livercancer.

In one embodiment, the DAC inhibitor or Panobinostat (Compound A19) isadministered at a dose of about 20 mg (e.g., per day).

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aninhibitor of one or more of cytochrome P450 (e.g., 11B2), aldosterone orangiogenesis, Osilodrostat (Compound A20), or a compound disclosed inPCT Publication No. WO2007/024945 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the inhibitor of one or more ofcytochrome P450 (e.g., 11B2), aldosterone or angiogenesis isOsilodrostat (Compound A20) or a compound disclosed in PCT PublicationNo. WO2007/024945. In one embodiment, a PD-1 antibody molecule is usedin combination with Osilodrostat (Compound A20), or a compound disclosedin PCT Publication No. WO2007/024945, to treat a disorder such asCushing's syndrome, hypertension, or heart failure therapy.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aIAP inhibitor,(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21) or a compound disclosed in U.S. Pat. No. 8,552,003 totreat a disorder, e.g., a disorder described herein. In one embodiment,the IAP inhibitor is(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21) or a compound disclosed in U.S. Pat. No. 8,552,003. Inone embodiment, a PD-1 antibody molecule is used in combination with(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21), or a compound disclosed in U.S. Pat. No. 8,552,003, totreat a disorder such as a multiple myeloma, a breast cancer, an ovariancancer, a pancreatic cancer, or a hematopoiesis disorder.

In one embodiment, the IAP inhibitor or(S)—N—((S)-1-cyclohexyl-2-((S)-2-(4-(4-fluorobenzoyl)thiazol-2-yl)pyrrolidin-1-yl)-2-oxoethyl)-2-(methylamino)propanamide(Compound A21) or a compound disclosed in U.S. Pat. No. 8,552,003 isadministered at a dose of approximately 1800 mg, e.g., once weekly.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination aSmoothened (SMO) inhibitor, Sonidegib phosphate (Compound A22),(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol(Compound A25), or a compound disclosed in PCT Publication No. WO2007/131201 or WO 2010/007120 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the SMO inhibitor is Sonidegibphosphate (Compound A22),(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol(Compound A25), or a compound disclosed in PCT Publication No. WO2007/131201 or WO 2010/007120. In one embodiment, a PD-1 antibodymolecule is used in combination with Sonidegib phosphate (Compound A22),(R)-2-(5-(4-(6-benzyl-4,5-dimethylpyridazin-3-yl)-2-methylpiperazin-1-yl)pyrazin-2-yl)propan-2-ol(Compound A25), or a compound disclosed in PCT Publication No. WO2007/131201 or WO 2010/007120 to treat a disorder such as a cancer, amedulloblastoma, a small cell lung cancer, a prostate cancer, a basalcell carcinoma, a pancreatic cancer, or an inflammation.

In certain embodiments, Sonidegib phosphate (Compound A22) isadministered at a dose of about 20 to 500 mg, e.g., about 40 mg to 400mg, about 50 mg to 300 mg, or about 100 mg to 200 mg, e.g., about 50 mg,100 mg, 150 mg, 200 mg, 250 mg, or 300 mg. The dosing schedule can varyfrom e.g., every other day to daily, twice or three times a day.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anAlk inhibitor, ceritinib (also known as ZYKADIA; Compound A23) or acompound disclosed in PCT Publication No. WO 2007/131201 to treat adisorder, e.g., a disorder described herein. In one embodiment, the Alkinhibitor is ceritinib (Compound A23) or a compound disclosed in PCTPublication No. WO 2007/131201. In one embodiment, a PD-1 antibodymolecule is used in combination with ceritinib (Compound A23), or acompound disclosed in PCT Publication No. WO 2007/131201, to treat adisorder such as non-small cell lung cancer or solid tumors.

In one embodiment, the Alk inhibitor or ceritinib (Compound A23) isadministered at a dose of approximately 750 mg, e.g., once daily.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aJAK and/or CDK4/6 inhibitor,7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24), or a compound disclosed in U.S. Pat. No. 8,415,355 orU.S. Pat. No. 8,685,980 to treat a disorder, e.g., a disorder describedherein. In one embodiment, the JAK and/or CDK4/6 inhibitor is7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24) or a compound disclosed in U.S. Pat. No. 8,415,355 orU.S. Pat. No. 8,685,980. In one embodiment, a PD-1 antibody molecule isused in combination with7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24), or a compound disclosed in U.S. Pat. No. 8,415,355 orU.S. Pat. No. 8,685,980, to treat a disorder such as a lymphoma, aneurologic cancer, a melanoma, a breast cancer, or a solid tumor.

In one embodiment, the JAK and/or CDK4/6 inhibitor or7-cyclopentyl-N,N-dimethyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A24) is administered at a dose of approximately 200-600 mg,e.g., per day. In one embodiment, the compound is administered at a doseof about 200, 300, 400, 500, or 600 mg, or about 200-300, 300-400,400-500, or 500-600 mg.

In another embodiment, the antibody molecule, e.g., an anti-PD-1antibody molecule as described herein, alone or in combination with oneor more other immunomodulators, is used in combination a prolactinreceptor (PRLR) inhibitor, a human monoclonal antibody molecule(Compound A26) as disclosed in U.S. Pat. No. 7,867,493), to treat adisorder, e.g., a disorder described herein. In one embodiment, the PRLRinhibitor is a human monoclonal antibody (Compound A26) disclosed inU.S. Pat. No. 7,867,493. In one embodiment, a PD-1 antibody molecule isused in combination with human monoclonal antibody molecule (CompoundA26) described in U.S. Pat. No. 7,867,493 to treat a disorder such as, acancer, a prostate cancer, or a breast cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aPIM Kinase inhibitor,N-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(Compound A27) or a compound disclosed in PCT Publication No. WO2010/026124 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the PIM Kinase inhibitor isN-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(Compound A27) or a compound disclosed in PCT Publication No. WO2010/026124. In one embodiment, a PD-1 antibody molecule is used incombination withN-(4-((1R,3S,5S)-3-amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide(Compound A27), or a compound disclosed in PCT Publication No. WO2010/026124, to treat a disorder such as a multiple myeloma,myelodysplastic syndrome, a myeloid leukemia, or a non-Hodgkin lymphoma.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination a Wntsignaling inhibitor,2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28) or a compound disclosed in PCT publication No. WO2010/101849 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the Wnt signaling inhibitor is2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28) or a compound disclosed in PCT publication No. WO2010/101849. In one embodiment, the Wnt signaling inhibitor is2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28). In one embodiment, a PD-1 antibody molecule is used incombination with2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28), or a compound disclosed in PCT publication No. WO2010/101849, to treat a disorder such as a solid tumor (e.g., a head andneck cancer, a squamous cell carcinoma, a breast cancer, a pancreaticcancer, or a colon cancer).

In certain embodiments,2-(2′,3-dimethyl-[2,4′-bipyridin]-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide(Compound A28) is administered at a dose of about 1 to 50 mg, e.g.,about 2 mg to 45 mg, about 3 mg to 40 mg, about 5 mg to 35 mg, 5 mg to10 mg, or about 10 mg to 30 mg, e.g., about 2 mg, 5 mg, 10 mg, 20 mg, 30mg, or 40 mg. The dosing schedule can vary from e.g., every other day todaily, twice or three times a day.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aBRAF inhibitor, Encorafenib (Compound A29), or a compound disclosed inPCT Publication No. WO 2011/025927 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the BRAF inhibitor is Encorafenib(Compound A29) or a compound disclosed in PCT Publication No. WO2011/025927. In one embodiment, a PD-1 antibody molecule is used incombination with Encorafenib (Compound A29), or a compound disclosed inPCT Publication No. WO 2011/025927, to treat a disorder such as anon-small cell lung cancer, a melanoma, or a colorectal cancer.

In one embodiment, the BRAF inhibitor or Encorafenib (Compound A29) isadministered at a dose of about 200-300, 200-400, or 300-400 mg, e.g.,per day. In one embodiment, the compound is administered at a dose ofabout 200, about 300 or about 400 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination a CDK4/6inhibitor,7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A30), or a compound disclosed in PCT publication No. WO2011/101409 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the CDK4/6 inhibitor is7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A30) or a compound disclosed in PCT publication No. WO2011/101409. In one embodiment, a PD-1 antibody molecule is used incombination with7-cyclopentyl-N,N-dimethyl-2-((5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(Compound A30), or a compound disclosed in PCT publication No. WO2011/101409, to treat a disorder such as a cancer, a mantle celllymphoma, a liposarcoma, a non-small cell lung cancer, a melanoma, asquamous cell esophageal cancer, or a breast cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aHER3 inhibitor, Compound A31, or a compound disclosed in PCT PublicationNo. WO 2012/022814, to treat a disorder, e.g., a disorder describedherein. In one embodiment, the HER3 inhibitor is Compound A31 or acompound disclosed in PCT Publication WO 2012/022814. In one embodiment,a PD-1 antibody molecule is used in combination with Compound A31, or acompound disclosed in PCT Publication WO 2012/022814, to treat adisorder such as a gastric cancer, an esophageal cancer, a head and neckcancer, a squamous cell carcinoma, a stomach cancer, a breast cancer(e.g., metastatic breast cancer), or a digestive/gastrointestinalcancer.

In some embodiments, Compound A31 is a human monoclonal antibodymolecule.

In one embodiment, the HER3 inhibitor or Compound A31 is administered ata dose of about 3, 10, 20, or 40 mg/kg, e.g., once weekly (QW). In oneembodiment, the compound is administered at a dose of about 3-10, 10-20,or 20-40 mg/kg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination an FGFR2and/or FGFR4 inhibitor, Compound A32, or a compound disclosed in apublication PCT Publication No. WO 2014/160160 (e.g., an antibodymolecule drug conjugate against an FGFR2 and/or FGFR4, e.g., mAb 12425),to treat a disorder, e.g., a disorder described herein. In oneembodiment, the FGFR2 and/or FGFR4 inhibitor is Compound A32 or acompound disclosed in a publication PCT Publication No. WO 2014/160160.In one embodiment, a PD-1 antibody molecule is used in combination withCompound A32, or a compound as described in Table 7, to treat a disordersuch as a cancer, a gastric cancer, a breast cancer, a rhabdomyosarcoma,a liver cancer, an adrenal cancer, a lung cancer, an esophageal cancer,a colon cancer, or an endometrial cancer.

In some embodiments, Compound A32 is an antibody molecule drug conjugateagainst an FGFR2 and/or FGFR4, e.g., mAb 12425.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination an M-CSFinhibitor, Compound A33, or a compound disclosed in PCT Publication No.WO 2004/045532 (e.g., an antibody molecule or Fab fragment againstM-CSF), to treat a disorder, e.g., a disorder described herein. In oneembodiment, the M-CSF inhibitor is Compound A33 or a compound disclosedin PCT Publication No. WO 2004/045532. In one embodiment, a PD-1antibody molecule is used in combination with Compound A33, or acompound as described in PCT Publication No. WO 2004/045532, to treat adisorder such as a cancer, a prostate cancer, a breast cancer, orpigmented villonodular synovitis (PVNS).

In embodiments, Compound A33 is a monoclonal antibody molecule againstM-CSF or a fragment (e.g., Fab fragment) thereof. In embodiments, theM-CSF inhibitor or Compound A33 is administered at an average dose ofabout 10 mg/kg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aMEK inhibitor, Binimetinib (Compound A34), or a compound disclosed inPCT Publication No. WO 2003/077914 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the MEK inhibitor is Binimetinib(Compound A34), or a compound disclosed in PCT Publication No. WO2003/077914. In one embodiment, a PD-1 antibody molecule is used incombination with Binimetinib (Compound A34), or a compound disclosed inPCT Publication No. WO 2003/077914, to treat a disorder such as anon-small cell lung cancer, a multisystem genetic disorder, a melanoma,an ovarian cancer, a digestive/gastrointestinal cancer, a rheumatoidarthritis, or a colorectal cancer.

In one embodiment, the MEK inhibitor or Binimetinib (Compound A34) isadministered at a dose of about 45 mg, e.g., twice daily.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination aninhibitor of one or more of c-KIT, histamine release, Flt3 (e.g.,FLK2/STK1) or PKC, Midostaurin (Compound A35) or a compound disclosed inPCT Publication No. WO 2003/037347 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the inhibitor is Midostaurin(Compound A35) or compound disclosed in PCT Publication No. WO2003/037347. In one embodiment, the inhibitor of one or more of c-KIT,histamine release, Flt3 (e.g., FLK2/STK1) or PKC is Midostaurin. In oneembodiment, a PD-1 antibody molecule is used in combination withMidostaurin (Compound A35), or compound disclosed in PCT Publication No.WO 2003/037347, to treat a disorder such as a cancer, a colorectalcancer, a myeloid leukemia, myelodysplastic syndrome, an age-relatedmascular degeration, a diabetic complication, or a dermatologicdisorder.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aTOR inhibitor (e.g., mTOR inhibitor), Everolimus (also known asAFINITOR; Compound A36) or a Compound disclosed in PCT Publication No.WO 2014/085318 to treat a disorder, e.g., a disorder described herein).In one embodiment, the TOR inhibitor is Everolimus (Compound A36) or aCompound disclosed in PCT Publication No. WO 2014/085318. In oneembodiment, a PD-1 antibody molecule is used in combination withEverolimus (Compound A36) to treat a disorder such as an interstitiallung disease, a small cell lung cancer, a respiratory/thoracic cancer, aprostate cancer, a multiple myeloma, a sarcoma, an age-related maculardegeneration, a bone cancer, tuberous sclerosis, a non-small cell lungcancer, an endocrine cancer, a lymphoma, a neurologic disorders, anastrocytoma, a cervical cancer, a neurologic cancer, a leukemia, animmune disorders, transplant rejection, a gastric cancer, a melanoma,epilepsy, a breast cancer, or a bladder cancer.

In one embodiment, the TOR inhibitor or Everolimusis (Compound A36)administered at a dose of about 2.5-20 mg/day. In one embodiment, thecompound is administered at a dose of about 2.5, 5, 10, or 20 mg/day,e.g., about 2.5-5, 5-10, or 10-20 mg/day.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination aninhibitor of one or more of VEGFR-2, PDGFRbeta, KIT or Raf kinase C,1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine(Compound A37) or a compound disclosed in PCT Publication No. WO2007/030377 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the inhibitor of one or more of VEGFR-2, PDGFRbeta, KITor Raf kinase C is1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine(Compound A37) or a compound disclosed in PCT Publication No. WO2007/030377. In one embodiment, a PD-1 antibody molecule is used incombination with1-methyl-5-((2-(5-(trifluoromethyl)-1H-imidazol-2-yl)pyridin-4-yl)oxy)-N-(4-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-2-amine(Compound A37), or a compound disclosed in PCT Publication No. WO2007/030377, to treat a disorder such as a cancer, a melanoma, or asolid tumor.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination asomatostatin agonist and/or growth hormone release inhibitor,Pasireotide diaspartate (also known as SIGNIFOR; Compound A38) or acompound disclosed in PCT Publication No. WO2002/010192 or U.S. Pat. No.7,473,761 to treat a disorder, e.g., a disorder described herein. In oneembodiment, the somatostatin agonist and/or growth hormone releaseinhibitor is Pasireotide diaspartate (Compound A38) or a compounddisclosed in PCT Publication No. WO2002/010192 or U.S. Pat. No.7,473,761. In one embodiment, a PD-1 antibody molecule is used incombination with Pasireotide diaspartate (Compound A38), or a compounddisclosed in PCT Publication No. WO2002/010192 or U.S. Pat. No.7,473,761, to treat a disorder such as a prostate cancer, an endocrinecancer, a nurologic cancer, a skin cancer (e.g., a melanoma), apancreatic cancer, a liver cancer, Cushing's syndrome, agastrointestinal disorder, acromegaly, a liver and biliary tractdisorder, or liver cirrhosis.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination a signaltransduction modulator and/or angiogenesis inhibitor, Dovitinib(Compound A39) or a compound disclosed in PCT Publication No. WO2009/115562 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the signal transduction modulator and/or angiogenesisinhibitor is Dovitinib (Compound A39) or a compound disclosed in PCTPublication No. WO 2009/115562. In one embodiment, a PD-1 antibodymolecule is used in combination with Dovitinib (Compound A39), or acompound disclosed in PCT Publication No. WO 2009/115562, to treat adisorder such as a cancer, a respiratory/thoracic cancer, a multiplemyeloma, a prostate cancer, a non-small cell lung cancer, an endocrinecancer, or a neurological genetic disorder.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anEGFR inhibitor,(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) or a compound disclosed in PCT Publication No. WO2013/184757 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the EGFR inhibitor is(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) or a compound disclosed in PCT Publication No. WO2013/184757. In one embodiment, a PD-1 antibody molecule is used incombination with(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40), or a compound disclosed in PCT Publication No. WO2013/184757, to treat a disorder such as a cancer, e.g., a solid tumor.

In one embodiment, the EGFR inhibitor or(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2-methylisonicotinamide(Compound A40) is administered at a dose of 150-250 mg, e.g., per day.In one embodiment, the compound is administered at a dose of about 150,200, or 250 mg, or about 150-200 or 200-250 mg.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination an ALKinhibitor,N⁶-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine(Compound A42) or a compound disclosed in PCT Publication No. WO2008/073687 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the ALK inhibitor isN⁶-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine(Compound A42) or a compound disclosed in PCT Publication No. WO2008/073687. In one embodiment, a PD-1 antibody molecule is used incombination withN⁶-(2-isopropoxy-5-methyl-4-(1-methylpiperidin-4-yl)phenyl)-N⁴-(2-(isopropylsulfonyl)phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine(Compound A42), or a compound disclosed in PCT Publication No. WO2008/073687, to treat a disorder such as a cancer, an anaplasticlarge-cell lymphoma (ALCL), a non-small cell lung carcinoma (NSCLC), ora neuroblastoma.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination anIGF-1R inhibitor,3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane1,1-dioxide (Compound A43),5-chloro-N²-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A44), or5-chloro-N²-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A45) or a compound disclosed in PCT Publication No. WO2010/002655 to treat a disorder, e.g., a disorder described. In oneembodiment, the IGF-1R inhibitor is3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane1,1-dioxide (Compound A43),5-chloro-N²-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A44),5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A45), or a compound disclosed in PCT Publication No. WO2010/002655. In one embodiment, a PD-1 antibody molecule is used incombination with3-(4-(4-((5-chloro-4-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)-5-fluoro-2-methylphenyl)piperidin-1-yl)thietane1,1-dioxide (Compound A43),5-chloro-N²-(2-fluoro-5-methyl-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl)phenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A44),5-chloro-N2-(4-(1-ethylpiperidin-4-yl)-2-fluoro-5-methylphenyl)-N⁴-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine(Compound A45), or a compound disclosed in PCT Publication No. WO2010/002655, to treat a disorder such as a cancer or a sarcoma.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination aP-Glycoprotein 1 inhibitor, Valspodar (also known as AMDRAY; CompoundA46) or a compound disclosed in EP 296122 to treat a disorder, e.g., adisorder described herein. In one embodiment, the P-Glycoprotein 1inhibitor is Valspodar (Compound A46) or a compound disclosed in EP296122. In one embodiment, a PD-1 antibody molecule is used incombination with Valspodar (Compound A46), or a compound disclosed in EP296122, to treat a disorder such as a cancer or a drug-resistant tumor.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination one ormore of a VEGFR inhibitor, Vatalanib succinate (Compound A47) or acompound disclosed in EP 296122 to treat a disorder, e.g., a disorderdescribed herein. In one embodiment, the VEGFR inhibitor is Vatalanibsuccinate (Compound A47) or a compound disclosed in EP 296122. In oneembodiment, a PD-1 antibody molecule is used in combination withVatalanib succinate (Compound A47), or a compound disclosed in EP296122, to treat cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anIDH inhibitor or a compound disclosed in WO2014/141104 to treat adisorder, e.g., a disorder described herein. In one embodiment, the IDHinhibitor is a compound disclosed in PCT Publication No. WO2014/141104.In one embodiment, a PD-1 antibody molecule is used in combination witha compound disclosed in WO2014/141104 to treat a disorder such as acancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with aBCL-ABL inhibitor or a compound disclosed in PCT Publication No.WO2013/171639, WO2013/171640, WO2013/171641, or WO2013/171642 to treat adisorder, e.g., a disorder described herein. In one embodiment, theBCL-ABL inhibitor is a compound disclosed in PCT Publication No.WO2013/171639, WO2013/171640, WO2013/171641, or WO2013/171642. In oneembodiment, a PD-1 antibody molecule is used in combination with acompound disclosed in PCT Publication No. WO2013/171639, WO2013/171640,WO2013/171641, or WO2013/171642 to treat a disorder such as a cancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with ac-RAF inhibitor or a compound disclosed in PCT Publication No.WO2014/151616 to treat a disorder, e.g., a disorder described herein. Inone embodiment, the c-RAF inhibitor is Compound A50 or a compounddisclosed in PCT Publication No. WO2014/151616. In one embodiment, aPD-1 antibody molecule is used in combination with a compound disclosedin PCT Publication No. WO2014/151616 to treat a disorder such as acancer.

In another embodiment, the anti-PD-1 antibody molecule, e.g., ananti-PD-1 antibody molecule as described herein, alone or in combinationwith one or more other immunomodulators, is used in combination with anERK1/2 ATP competitive inhibitor or a compound disclosed inInternational Patent Application No. PCT/US2014/062913 to treat adisorder, e.g., a disorder described herein. In one embodiment, theERK1/2 ATP competitive inhibitor is a compound disclosed inInternational Patent Application No. PCT/US2014/062913. In oneembodiment, a PD-1 antibody molecule is used in combination withCompound A51 or a compound disclosed in International Patent ApplicationNo. PCT/US2014/062913 to treat a disorder such as a cancer.

In some embodiments, the PD-1 antibody molecule is administered incombination with one or more agents selected from, Compound A8, CompoundA17, Compound A23, Compound A24, Compound A27, Compound A29, andCompound A33.

In some embodiments, a PD-1 antibody molecule is administered incombination with an anti-cancer agent having a known activity in animmune cell assay, e.g., in one or more of a huMLR assay, a T cellproliferation assay, and a B-cell proliferation assay. Exemplary assaysare described below. Based on the assay, an IC50 for can be calculatedfor each test agent. In embodiments, the anti-cancer agent has an IC50of, e.g., 0-1 μM, 1-4 μM, or greater than 4 μM, e.g., 4-10 μM or 4-20μM. In embodiments, the second therapeutic agent is chosen from one ormore of: Compound A9, Compound A16, Compound A17, Compound A21, CompoundA22, Compound A25, Compound A28, Compound A48, and Compound 49.

In some embodiments, the Compound A28 (or a compound related to CompoundA28) is administered at a dose of approximately 5-10 or 10-30 mg. Insome embodiments, the Compound A22 (or compound related to Compound A22)is administered at a dose of about 200 mg. In some embodiments, theCompound A17 (or compound related to Compound A17) is administered at adose of approximately 400-600 mg. In some embodiments, the Compound A16(or compound related to Compound A16) is administered at a dose ofapproximately 400-600 mg PO qDay. In some embodiments, the Compound A29(or compound related to Compound A29) is administered at a dose ofapproximately 200-400 or 300-400 mg. In some embodiments, the CompoundA24 (or compound related to Compound A24) is administered at a dose ofapproximately 200-600 mg. In some embodiments, the Compound A23(ceritinib) (or compound related to ceritinib) is administered at a doseof approximately 750 mg once daily. In some embodiments, the Compound A8(or compound related to Compound A8) is administered at a dose ofapproximately 200-400 or 300-400 mg. In some embodiments, the CompoundA5 (or compound related to Compound A5) is administered at a dose ofapproximately 100-125 mg. In some embodiments, the Compound A6 (orcompound related to Compound A6) is administered at a dose of about 100mg. In some embodiments, the Compound A1 (or compound related toCompound A1) is administered at a dose of approximately 200-300 or200-600 mg. In some embodiments, the Compound A40 (or compound relatedto Compound A40) is administered at a dose of approximately 150-250 mg.In embodiments, the Compound A10 (or compound related to Compound A10)is administered at a dose of approximately 400 to 700 mg, e.g.,administered three times weekly, 2 weeks on and one week off. Inembodiments, the BCR-ABL inhibitor is administered at a dose ofapproximately 20 mg bid-80 mg bid.

Exemplary huMLR assay and B or T cell proliferation assays are providedbelow.

Human Mixed Lymphocyte Reaction

The Mixed Lymphocyte Reaction (MLR) is a functional assay which measuresthe proliferative response of lymphocytes from one individual (theresponder) to lymphocytes from another individual (the stimulator). Toperform an allogeneic MLR, peripheral blood mononuclear cells (PBMC)from three donors were isolated from buffy-coats of unknown HLA type(Kantonspital Blutspendezentrum from Bern and Aarau, Switzerland). Thecells were prepared at 2.105 in 0.2 mL of culture medium containing RPMI1640 GlutaMAX™ with 10% fetal calf serum (FCS), 100U penicillin/100 μgstreptomycin, 50 μM 2-Mercaptoethanol. Individual 2-way reactions wereset up by mixing PBMC from two different donors at a 1:1 ratio andco-cultures were done in triplicates in flat-bottomed 96-well tissueculture plates for 6 days at 37° C., 5% CO2, in presence or not of an8-point concentration range of test compounds. Cells were pulsed with3H-TdR (1 μCi/0.2 mL) for the last 16h of culture and incorporatedradioactivity was used as a measure of cell proliferation. Theconcentration that inhibited 50% of the maximal huMLR response (IC50)was calculated for each compound. Cyclosporine was used as a positivecontrol of huMLR inhibition.

Human B Cell Proliferation Assay

PBMC were freshly isolated by Ficoll-Paque density gradient from humanblood and subjected to negative B-cell isolation. B cells wereresuspended in culture medium (RPMI 1640, HEPES, 10% FCS, 50m/mLgentamicine, 50 μM 2-Mercaptoethanol, 1×ITS (Insulin, Transferrin andSodium Selenite), 1× Non-Essential Amino-Acids) at a concentration of9.104 per well in a flat-bottom 96-well culture plate. B cellstimulation was performed by human anti-IgM antibody molecule (30 ug/mL)and IL-4 (75 ng/mL) or by CD40 ligand (3 ug/mL) and IL-4 (75 ng/mL) inpresence or not of a 7-point concentration range of test compounds.After 72h of culture at 37° C., 10% CO2, cells were pulsed with 3H-TdR(1 Xi/well) for the last 6h of culture. B cells were then harvested andthe incorporation of thymidine was measured using a scintillationcounter. Of each duplicate treatment, the mean was calculated and thesedata were plotted in XLfit 4 to determine the respective IC50 values.

Human T Cell Proliferation Assay

PBMC were freshly isolated by Ficoll-Paque density gradient from humanblood and subjected to negative isolation of T cells. T cells wereprepared in culture medium (RPMI 1640, HEPES, 10% FCS, 50m/mLgentamicine, 50 μM 2-Mercaptoethanol, 1×ITS (Insulin, Transferrin andSodium Selenite), 1× Non-Essential Amino-Acids) at a concentration of8.104 per well in a flat-bottom 96-well culture plate. T cellstimulation was performed by human anti-CD3 antibody molecule (10 ug/mL)or by human anti-CD3 antibody molecule (5m/mL) and anti-CD28 antibodymolecule (1m/mL) in presence or not of a 7-point concentration range oftest compounds. After 72h of culture at 37° C., 10% CO2, cells werepulsed with 3H-TdR (1 Xi/well) for the last 6h of culture. Cellproliferation was measured by the incorporation of thymidine allowingIC50 determination for each tested compound.

Down-Modulators of the Immune System

In an alternative embodiment, the anti-PD-1 antibody molecules disclosedherein are used to produce anti-idiotypic peptides or antibodies(Wallmann, J. et al. (2010) “Anti-Ids in Allergy: Timeliness of aClassic Concept,” World Allergy Organiz. J. 3(6):195-201; Nardi, M. etal. (2000) “Antiidiotype Antibody Against Platelet Anti-GpiiiaContributes To The Regulation Of Thrombocytopenia In HIV-1-ITPPatients,” J. Exp. Med. 191(12):2093-2100) or mimetics (Zang, Y. C. etal. (2003) “Human Anti-Idiotypic T Cells Induced By TCR PeptidesCorresponding To A Common CDR3Sequence Motif In Myelin BasicProtein-Reactive T Cells,” Int. Immunol. 15(9):1073-1080; Loiarro, M. etal. (Epub 2010 Apr. 8) “Targeting TLR/IL-1R Signalling In HumanDiseases,” Mediators Inflamm. 2010:674363) of B7-H1 or PD-1. Suchmolecules serve as surrogates for PD-1, and thus their administration toa subject down-modulates the immune system of such subject by mimickingor facilitating B7-H1-PD-1 binding. Such molecules have utility in thetreatment of graft vs. host disease. Similarly, agonist antibodies thati) enhance binding between such antibodies and such receptor/ligand orii) trigger signal transduction when bound directly to B7-H1 or PD-1,have utility as agonists of B7-H1-PD-1 signaling and thus have utilityin the treatment of inflammation and autoimmune disease, by directly orindirectly agonizing receptor activity.

Bispecific antibodies, exhibiting immunospecific binding to both PD-1and B7-H1 are capable of binding to both APC and T-cells, and thusfacilitate the co-localization of APCs and T-cells. Such co-localizationfacilitates the ability of such cells to bind together via B7-H1 andPD-1 molecules that are not complexed with antibody, or by co-inhibitorymolecules. Such binding provides down modulation of the immune system ofthe recipient.

Down-modulation of the immune system is desirable in the treatment ofinflammatory and auto-immune diseases, and graft vs. host disease(GvHD). Examples of autoimmune disorders that may be treated byadministering the antibodies of the present invention include, but arenot limited to, alopecia greata, ankylosing spondylitis,antiphospholipid syndrome, autoimmune Addison's disease, autoimmunediseases of the adrenal gland, autoimmune hemolytic anemia, autoimmunehepatitis, autoimmune oophoritis and orchitis, autoimmunethrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy,celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome(CFIDS), chronic inflammatory demyelinating polyneuropathy,Churg-Strauss syndrome, cicatrical pemphigoid, CREST syndrome, coldagglutinin disease, Crohn's disease, discoid lupus, essential mixedcryoglobulinemia, fibromyalgia-fibromyositis, glomerulonephritis,Graves' disease, Guillain-Barre, Hashimoto's thyroiditis, idiopathicpulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgAneuropathy, juvenile arthritis, lichen planus, lupus erthematosus,Meniere's disease, mixed connective tissue disease, multiple sclerosis,Neuromyelitis optica (NMO), type 1 or immune-mediated diabetes mellitus,myasthenia gravis, pemphigus vulgaris, pernicious anemia, polyarteritisnodosa, polychrondritis, polyglandular syndromes, polymyalgiarheumatica, polymyositis and dermatomyositis, primaryagammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriaticarthritis, Raynauld's phenomenon, Reiter's syndrome, Rheumatoidarthritis, sarcoidosis, scleroderma, Sjogren's syndrome, stiff-mansyndrome, systemic lupus erythematosus, lupus erythematosus, takayasuarteritis, temporal arteristis/giant cell arteritis, transversemyelitis, ulcerative colitis, uveitis, vasculitides such as dermatitisherpetiformis vasculitis, vitiligo, and Wegener's granulomatosis.

Examples of inflammatory disorders which can be prevented, treated ormanaged in accordance with the methods of the invention include, but arenot limited to, asthma, encephilitis, inflammatory bowel disease,chronic obstructive pulmonary disease (COPD), allergic disorders, septicshock, pulmonary fibrosis, undifferentiated spondyloarthropathy,undifferentiated arthropathy, arthritis, inflammatory osteolysis, andchronic inflammation resulting from chronic viral or bacterialinfections.

Thus, the antibodies and antigen-binding fragments of the presentinvention have utility in the treatment of inflammatory and autoimmunediseases.

Diagnostic Uses

In one aspect, the present invention provides a diagnostic method fordetecting the presence of a PD-1 protein in vitro (e.g., in a biologicalsample, such as a tissue biopsy, e.g., from a cancerous tissue) or invivo (e.g., in vivo imaging in a subject). The method includes: (i)contacting the sample with an antibody molecule described herein, oradministering to the subject, the antibody molecule; (optionally) (ii)contacting a reference sample, e.g., a control sample (e.g., a controlbiological sample, such as plasma, tissue, biopsy) or a controlsubject)); and (iii) detecting formation of a complex between theantibody molecule, and the sample or subject, or the control sample orsubject, wherein a change, e.g., a statistically significant change, inthe formation of the complex in the sample or subject relative to thecontrol sample or subject is indicative of the presence of PD-1 in thesample. The antibody molecule can be directly or indirectly labeled witha detectable substance to facilitate detection of the bound or unboundantibody. Suitable detectable substances include various enzymes,prosthetic groups, fluorescent materials, luminescent materials andradioactive materials, as described above and described in more detailbelow.

The term “sample,” as it refers to samples used for detectingpolypeptides includes, but is not limited to, cells, cell lysates,proteins or membrane extracts of cells, body fluids, or tissue samples.

Complex formation between the antibody molecule and PD-1 can be detectedby measuring or visualizing either the binding molecule bound to thePD-1 antigen or unbound binding molecule. Conventional detection assayscan be used, e.g., an enzyme-linked immunosorbent assays (ELISA), aradioimmunoassay (RIA) or tissue immunohistochemistry.

Alternative to labeling the antibody molecule, the presence of PD-1 canbe assayed in a sample by a competition immunoassay utilizing standardslabeled with a detectable substance and an unlabeled antibody molecule.In this assay, the biological sample, the labeled standards and theantibody molecule are combined and the amount of labeled standard boundto the unlabeled binding molecule is determined. The amount of PD-1 inthe sample is inversely proportional to the amount of labeled standardbound to the antibody molecule.

Nucleic Acids

The invention also features nucleic acids comprising nucleotidesequences that encode heavy and light chain variable regions and CDRs orhypervariable loops of the anti-PD-1 antibody molecules, as describedherein. For example, the invention features a first and second nucleicacid encoding heavy and light chain variable regions, respectively, ofan anti-PD-1 antibody molecule chosen from one or more of the antibodymolecules disclosed herein. The nucleic acid can comprise a nucleotidesequence as set forth in the tables herein, or a sequence substantiallyidentical thereto (e.g., a sequence at least about 85%, 90%, 95%, 99% ormore identical thereto, or which differs by no more than 3, 6, 15, 30,or 45 nucleotides from the sequences shown in the tables herein.

In certain embodiments, the nucleic acid can comprise a nucleotidesequence encoding at least one, two, or three CDRs or hypervariableloops from a heavy chain variable region having an amino acid sequenceas set forth in the tables herein, or a sequence substantiallyhomologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%or more identical thereto, and/or having one or more substitutions,e.g., conserved substitutions). In other embodiments, the nucleic acidcan comprise a nucleotide sequence encoding at least one, two, or threeCDRs or hypervariable loops from a light chain variable region having anamino acid sequence as set forth in the tables herein, or a sequencesubstantially homologous thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, and/or having one or moresubstitutions, e.g., conserved substitutions). In yet anotherembodiment, the nucleic acid can comprise a nucleotide sequence encodingat least one, two, three, four, five, or six CDRs or hypervariable loopsfrom heavy and light chain variable regions having an amino acidsequence as set forth in the tables herein, or a sequence substantiallyhomologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%or more identical thereto, and/or having one or more substitutions,e.g., conserved substitutions).

In certain embodiments, the nucleic acid can comprise a nucleotidesequence encoding at least one, two, or three CDRs or hypervariableloops from a heavy chain variable region having the nucleotide sequenceas set forth in the tables herein, a sequence substantially homologousthereto (e.g., a sequence at least about 85%, 90%, 95%, 99% or moreidentical thereto, and/or capable of hybridizing under the stringencyconditions described herein). In another embodiment, the nucleic acidcan comprise a nucleotide sequence encoding at least one, two, or threeCDRs or hypervariable loops from a light chain variable region havingthe nucleotide sequence as set forth in the tables herein, or a sequencesubstantially homologous thereto (e.g., a sequence at least about 85%,90%, 95%, 99% or more identical thereto, and/or capable of hybridizingunder the stringency conditions described herein). In yet anotherembodiment, the nucleic acid can comprise a nucleotide sequence encodingat least one, two, three, four, five, or six CDRs or hypervariable loopsfrom heavy and light chain variable regions having the nucleotidesequence as set forth in the tables herein, or a sequence substantiallyhomologous thereto (e.g., a sequence at least about 85%, 90%, 95%, 99%or more identical thereto, and/or capable of hybridizing under thestringency conditions described herein).

In another aspect, the application features host cells and vectorscontaining the nucleic acids described herein. The nucleic acids may bepresent in a single vector or separate vectors present in the same hostcell or separate host cell, as described in more detail hereinbelow.

Vectors

Further provided herein are vectors comprising nucleotide sequencesencoding an antibody molecule described herein. In one embodiment, thevectors comprise nucleotides encoding an antibody molecule describedherein. In one embodiment, the vectors comprise the nucleotide sequencesdescribed herein. The vectors include, but are not limited to, a virus,plasmid, cosmid, lambda phage or a yeast artificial chromosome (YAC).

Numerous vector systems can be employed. For example, one class ofvectors utilizes DNA elements which are derived from animal viruses suchas, for example, bovine papilloma virus, polyoma virus, adenovirus,vaccinia virus, baculovirus, retroviruses (Rous Sarcoma Virus, MMTV orMOMLV) or SV40 virus. Another class of vectors utilizes RNA elementsderived from RNA viruses such as Semliki Forest virus, Eastern EquineEncephalitis virus and Flaviviruses.

Additionally, cells which have stably integrated the DNA into theirchromosomes may be selected by introducing one or more markers whichallow for the selection of transfected host cells. The marker mayprovide, for example, prototropy to an auxotrophic host, biocideresistance (e.g., antibiotics), or resistance to heavy metals such ascopper, or the like. The selectable marker gene can be either directlylinked to the DNA sequences to be expressed, or introduced into the samecell by cotransformation. Additional elements may also be needed foroptimal synthesis of mRNA. These elements may include splice signals, aswell as transcriptional promoters, enhancers, and termination signals.

Once the expression vector or DNA sequence containing the constructs hasbeen prepared for expression, the expression vectors may be transfectedor introduced into an appropriate host cell. Various techniques may beemployed to achieve this, such as, for example, protoplast fusion,calcium phosphate precipitation, electroporation, retroviraltransduction, viral transfection, gene gun, lipid based transfection orother conventional techniques. In the case of protoplast fusion, thecells are grown in media and screened for the appropriate activity.

Methods and conditions for culturing the resulting transfected cells andfor recovering the antibody molecule produced are known to those skilledin the art, and may be varied or optimized depending upon the specificexpression vector and mammalian host cell employed, based upon thepresent description.

Cells

The invention also provides host cells comprising a nucleic acidencoding an antibody molecule as described herein.

In one embodiment, the host cells are genetically engineered to comprisenucleic acids encoding the antibody molecule.

In one embodiment, the host cells are genetically engineered by using anexpression cassette. The phrase “expression cassette,” refers tonucleotide sequences, which are capable of affecting expression of agene in hosts compatible with such sequences. Such cassettes may includea promoter, an open reading frame with or without introns, and atermination signal. Additional factors necessary or helpful in effectingexpression may also be used, such as, for example, an induciblepromoter.

The invention also provides host cells comprising the vectors describedherein.

The cell can be, but is not limited to, a eukaryotic cell, a bacterialcell, an insect cell, or a human cell. Suitable eukaryotic cellsinclude, but are not limited to, Vero cells, HeLa cells, COS cells, CHOcells, HEK293 cells, BHK cells and MDCKII cells. Suitable insect cellsinclude, but are not limited to, Sf9 cells.

TABLE 1 Amino acid and nucleotide sequences for murine, chimeric andhumanized antibody molecules. The antibody molecules include murine mAbBAP049, chimeric mAbs BAP049-chi and BAP049-chi-Y, and humanized mAbsBAP049-hum01 to BAP049-hum16 and BAP049- Clone-A to BAP049-Clone-E. Theamino acid and nucleotide sequences of the heavy and light chain CDRs,the heavy and light chain variable regions, and the heavy and lightchains are shown. BAP049 HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO:2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAYSEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGGSEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 6 VHQVQLQQPGSELVRPGASVKLSCKASGYTFTTYW MHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKNRTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRW TTGTGAYWGQGTLVTVSA SEQ ID NO: 7 DNA VHCAGGTCCAGCTGCAGCAACCTGGGTCTGAGCTG GTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCGTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGAGGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAAAACAGGACCTCACTGACTGTAGACACATCCTCCACC ACAGCCTACATGCACCTCGCCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAAGGGACTCTGGTCACTGTCTCTGCA SEQ ID NO: 8 VH QVQLQQSGSELVRPGASVKLSCKASGYTFTTYWMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKN RTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRWTTGTGAYWGQGTLVTVSA SEQ ID NO: 9 DNA VH CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCTGGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGC AAGGCGTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGAGGCAGAGGCCTGGACAAGGC CTTGAGTGGATTGGAAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAAAAC AGGACCTCACTGACTGTAGACACATCCTCCACCACAGCCTACATGCACCTCGCCAGCCTGACATCT GAGGACTCTGCGGTCTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAAGGG ACTCTGGTCACTGTCTCTGCA BAP049 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 12 (Kabat) LCDR3 QNDYSYPCT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 15(Chothia) LCDR3 DYSYPC SEQ ID NO: 16 VLDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDSG NQKNFLTWYQQKPGQPPKLLIFWASTRESGVPDRFTGSGSVTDFTLTISSVQAEDLAVYYCQNDYS YPCTFGGGTKLEIK SEQ ID NO: 17 DNA VLGACATTGTGATGACCCAGTCTCCATCCTCCCTG ACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTTC TGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGTAACAGATTTC ACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGT TATCCGTGCACGTTCGGAGGGGGGACCAAGCTGGAAATAAAA BAP049-chi HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2(Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO: 18 VHQVQLQQPGSELVRPGASVKLSCKASGYTFTTYW MHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKNRTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 19 DNAVH CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCTG GTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCGTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGAGGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAAAACAGGACCTCACTGACTGTAGACACATCCTCCACC ACAGCCTACATGCACCTCGCCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 20 HC QVQLQQPGSELVRPGASVKLSCKASGYTFTTYWMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKN RTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 21 DNA HC CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCTGGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGC AAGGCGTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGAGGCAGAGGCCTGGACAAGGC CTTGAGTGGATTGGAAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAAAAC AGGACCTCACTGACTGTAGACACATCCTCCACCACAGCCTACATGCACCTCGCCAGCCTGACATCT GAGGACTCTGCGGTCTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA SEQ ID NO: 22 VHQVQLQQSGSELVRPGASVKLSCKASGYTFTTYW MHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKNRTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 23 DNAVH CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCTG GTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCGTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGAGGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAAAACAGGACCTCACTGACTGTAGACACATCCTCCACC ACAGCCTACATGCACCTCGCCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC QVQLQQSGSELVRPGASVKLSCKASGYTFTTYWMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKN RTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HC CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCTGGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGC AAGGCGTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGAGGCAGAGGCCTGGACAAGGC CTTGAGTGGATTGGAAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAAAAC AGGACCTCACTGACTGTAGACACATCCTCCACCACAGCCTACATGCACCTCGCCAGCCTGACATCT GAGGACTCTGCGGTCTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-chi LC SEQ ID NO:10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRESSEQ ID NO: 12 (Kabat) LCDR3 QNDYSYPCT SEQ ID NO: 13 (Chothia) LCDR1SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 15 (Chothia)LCDR3 DYSYPC SEQ ID NO: 24 VL DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDSGNQKNFLTWYQQKPGQPPKLLIFWASTRESGVPD RFTGSGSVTDFTLTISSVQAEDLAVYYCQNDYSYPCTFGQGTKVEIK SEQ ID NO: 25 DNA VL GACATTGTGATGACCCAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCAGGGCAGCCTCCTAAACTGTTGATCTTCTGGGCATCCACTAGGGAATCTGGGGTCCCTGAT CGCTTCACAGGCAGTGGATCTGTAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGAC CTGGCAGTTTATTACTGTCAGAATGATTATAGTTATCCGTGCACGTTCGGCCAAGGGACCAAGGTG GAAATCAAA SEQ ID NO: 26 LCDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDSG NQKNFLTWYQQKPGQPPKLLIFWASTRESGVPDRFTGSGSVTDFTLTISSVQAEDLAVYYCQNDYS YPCTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 27 DNA LCGACATTGTGATGACCCAGTCTCCATCCTCCCTG ACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTTC TGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGTAACAGATTTC ACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGT TATCCGTGCACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTC TTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAAT AACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCC CAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTG AGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCG CCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTBAP049-chi-Y HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat)HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4(Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3(Chothia) HCDR3 WTTGTGAY SEQ ID NO: 18 VHQVQLQQPGSELVRPGASVKLSCKASGYTFTTYW MHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKNRTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 19 DNAVH CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCTG GTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCGTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGAGGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAAAACAGGACCTCACTGACTGTAGACACATCCTCCACC ACAGCCTACATGCACCTCGCCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 20 HC QVQLQQPGSELVRPGASVKLSCKASGYTFTTYWMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKN RTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 21 DNA HC CAGGTCCAGCTGCAGCAGCCTGGGTCTGAGCTGGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGC AAGGCGTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGAGGCAGAGGCCTGGACAAGGC CTTGAGTGGATTGGAAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAAAAC AGGACCTCACTGACTGTAGACACATCCTCCACCACAGCCTACATGCACCTCGCCAGCCTGACATCT GAGGACTCTGCGGTCTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA SEQ ID NO: 22 VHQVQLQQSGSELVRPGASVKLSCKASGYTFTTYW MHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKNRTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 23 DNAVH CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCTG GTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGCAAGGCGTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGAGGCAGAGGCCTGGACAAGGCCTTGAGTGGATTGGAAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAAAACAGGACCTCACTGACTGTAGACACATCCTCCACC ACAGCCTACATGCACCTCGCCAGCCTGACATCTGAGGACTCTGCGGTCTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 30 HC QVQLQQSGSELVRPGASVKLSCKASGYTFTTYWMHWVRQRPGQGLEWIGNIYPGTGGSNFDEKFKN RTSLTVDTSSTTAYMHLASLTSEDSAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 31 DNA HC CAGGTCCAGCTGCAGCAGTCTGGGTCTGAGCTGGTGAGGCCTGGAGCTTCAGTGAAGCTGTCCTGC AAGGCGTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGAGGCAGAGGCCTGGACAAGGC CTTGAGTGGATTGGAAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAAAAC AGGACCTCACTGACTGTAGACACATCCTCCACCACAGCCTACATGCACCTCGCCAGCCTGACATCT GAGGACTCTGCGGTCTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-chi-Y LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 34 VLDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDSG NQKNFLTWYQQKPGQPPKLLIFWASTRESGVPDRFTGSGSVTDFTLTISSVQAEDLAVYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 35 DNA VLGACATTGTGATGACCCAGTCTCCATCCTCCCTG ACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTTC TGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGTAACAGATTTC ACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 36 LC DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLDSGNQKNFLTWYQQKPGQPPKLLIFWASTRESGVPD RFTGSGSVTDFTLTISSVQAEDLAVYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 37DNA LC GACATTGTGATGACCCAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCAGGGCAGCCTCCTAAACTGTTGATCTTCTGGGCATCCACTAGGGAATCTGGGGTCCCTGAT CGCTTCACAGGCAGTGGATCTGTAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGAC CTGGCAGTTTATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum01 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum01 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 42 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 43 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTC ACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 44 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 45DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCATCA AGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATGAT TTTGCAACTTATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum02 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum02 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 46 VLDIQMTQSPSSLSASVGDRVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 47 DNA VLGACATCCAGATGACCCAGTCTCCATCCTCCCTG TCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTT ACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 48 LC DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGIPP RFSGSGYGTDFTLTINNIESEDAAYYFCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 49DNA LC GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACT TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGATCCCACCT CGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGAT GCTGCATATTACTTCTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum03 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGATCAGGCAGTCCCCATCGAGAGGC CTTGAGTGGCTGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum03 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 46 VLDIQMTQSPSSLSASVGDRVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 47 DNA VLGACATCCAGATGACCCAGTCTCCATCCTCCCTG TCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAACAGATTTT ACCCTCACAATTAATAACATAGAATCTGAGGATGCTGCATATTACTTCTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 48 LC DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGIPP RFSGSGYGTDFTLTINNIESEDAAYYFCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 49DNA LC GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACT TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGATCCCACCT CGATTCAGTGGCAGCGGGTATGGAACAGATTTTACCCTCACAATTAATAACATAGAATCTGAGGAT GCTGCATATTACTTCTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum04 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGATCAGGCAGTCCCCATCGAGAGGC CTTGAGTGGCTGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum04 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 54 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 55 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTT ACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 56 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 57DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTATCAGCAG AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCATCA AGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGAT ATTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum05 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum05 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 54 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 55 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGACAGATTTT ACTTTCACCATCAGCAGCCTGCAGCCTGAAGATATTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 56 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 57DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTATCAGCAG AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCATCA AGGTTCAGTGGAAGTGGATCTGGGACAGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAGAT ATTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum06 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum06 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 58 VLDIVMTQTPLSLPVTPGEPASISCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 59 DNA VLGATATTGTGATGACCCAGACTCCACTCTCCCTG CCCGTCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 60 LC DIVMTQTPLSLPVTPGEPASISCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 61DNA LC GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum07 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum07 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 62 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 63 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 64 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 65DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTATCAGCAG AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum08 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGATCAGGCAGTCCCCATCGAGAGGC CTTGAGTGGCTGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum08 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VLEIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 67 DNA VLGAAATTGTGCTGACTCAGTCTCCAGACTTTCAG TCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 LC EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum09 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum09 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VLEIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 67 DNA VLGAAATTGTGCTGACTCAGTCTCCAGACTTTCAG TCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 LC EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum10 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:50 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 51 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 52 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 53 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGATCAGGCAGTCCCCATCGAGAGGC CTTGAGTGGCTGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum10 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 71 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 72 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 73DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum11 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum11 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 71 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 72 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 73DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum12 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum12 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 74 VLDIQMTQSPSSLSASVGDRVTITCKSSQSLLDSG NQKNFLTWYLQKPGQSPQLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 75 DNA VLGACATCCAGATGACCCAGTCTCCATCCTCCCTG TCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 76 LC DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYLQKPGQSPQLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 77DNA LC GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACT TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCTGCAG AAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum13 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 39 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGAGTCACGATTACCGCGGACAAATCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 40 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 41 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCACTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGAGTCACGATTACCGCGGACAAATCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCT GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum13 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 78 VLDVVMTQSPLSLPVTLGQPASISCKSSQSLLDSG NQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 79 DNA VLGATGTTGTGATGACTCAGTCTCCACTCTCCCTG CCCGTCACCCTTGGACAGCCGGCCTCCATCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTAACCTGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCTGATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 80 LC DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 81DNA LC GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCTTGGACAGCCGGCCTCCATCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTAACCTGGTATCAGCAG AAACCAGGGAAAGCTCCTAAGCTCCTGATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum14 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:82 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 83 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTG AAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 84 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 85 DNA HC CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGC AAGGCTTCTGGCTACACATTCACCACTTACTGGATGCACTGGATCAGGCAGTCCCCATCGAGAGGC CTTGAGTGGCTGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTACTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum14 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 70 VLEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 71 DNA VLGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 72 LC EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 73DNA LC GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum15 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:82 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 83 DNA VHCAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTG AAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTACTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 84 HC QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 85 DNA HC CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGC AAGGCTTCTGGCTACACATTCACCACTTACTGGATGCACTGGATCAGGCAGTCCCCATCGAGAGGC CTTGAGTGGCTGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTACTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum15 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VLEIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 67 DNA VLGAAATTGTGCTGACTCAGTCTCCAGACTTTCAG TCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 LC EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-hum16 HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:86 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 87 DNA VHGAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTG AAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCTGGCTACACATTCACCACTTACTGG ATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGTAATATTTATCCTGGTACT GGTGGTTCTAACTTCGATGAGAAGTTCAAGAACAGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTACAAGATGG ACTACTGGGACGGGAGCTTATTGGGGCCAGGGCACCACCGTGACCGTGTCCTCC SEQ ID NO: 88 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKFKN RFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK SEQ ID NO: 89 DNA HC GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAAGCCCGGGGAGTCTCTGAGGATCTCCTGT AAGGGTTCTGGCTACACATTCACCACTTACTGGATGCACTGGGTGCGACAGGCCCCTGGACAAGGG CTTGAGTGGATGGGTAATATTTATCCTGGTACTGGTGGTTCTAACTTCGATGAGAAGTTCAAGAAC AGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCC GAGGACACGGCCGTGTATTACTGTACAAGATGGACTACTGGGACGGGAGCTTATTGGGGCCAGGGC ACCACCGTGACCGTGTCCTCCGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCGCCCTGCTCC AGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACGAAGACCTAC ACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGT CCCCCATGCCCACCGTGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCA AAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGC CAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG GACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTGTCCAACAAAGGCCTCCCGTCCTCCATCGAG AAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAG GAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATC GCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGAC TCCGACGGCTCCTTCTTCCTCTACAGCAGGCTAACCGTGGACAAGAGCAGGTGGCAGGAGGGGAAT GTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTG TCTCTGGGTAAA BAP049-hum16 LC SEQ IDNO: 10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2WASTRES SEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia)LCDR1 SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33(Chothia) LCDR3 DYSYPY SEQ ID NO: 66 VLEIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIK SEQ ID NO: 67 DNA VLGAAATTGTGCTGACTCAGTCTCCAGACTTTCAG TCTGTGACTCCAAAGGAGAAAGTCACCATCACCTGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGA AATCAAAAGAACTTCTTGACCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT TGGGCATCCACTAGGGAATCTGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGACAGATTTC ACCTTTACCATCAGTAGCCTGGAAGCTGAAGATGCTGCAACATATTACTGTCAGAATGATTATAGT TATCCGTACACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA SEQ ID NO: 68 LC EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69DNA LC GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGTGACTCCAAAGGAGAAAGTCACCATCACC TGCAAGTCCAGTCAGAGTCTGTTAGACAGTGGAAATCAAAAGAACTTCTTGACCTGGTACCAGCAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATTGGGCATCCACTAGGGAATCTGGGGTCCCCTCG AGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAGAT GCTGCAACATATTACTGTCAGAATGATTATAGTTATCCGTACACGTTCGGCCAAGGGACCAAGGTG GAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAA TCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGG AAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGAC AGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTAC GCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT BAP049-Clone-A HC SEQ ID NO: 1 (Kabat)HCDR1 TYWMH SEQ ID NO: 2 (Kabat) HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3(Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4 (Chothia) HCDR1 GYTFTTY SEQ ID NO: 5(Chothia) HCDR2 YPGTGG SEQ ID NO: 3 (Chothia) HCDR3 WTTGTGAY SEQ ID NO:38 VH EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS SEQ ID NO: 90 DNA VHGAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTCTGGCTACACCTTCACCACCTACTGG ATGCACTGGGTGCGACAGGCTACCGGCCAGGGCCTGGAATGGATGGGCAACATCTATCCTGGCACC GGCGGCTCCAACTTCGACGAGAAGTTCAAGAACAGAGTGACCATCACCGCCGACAAGTCCACCTCC ACCGCCTACATGGAACTGTCCTCCCTGAGATCCGAGGACACCGCCGTGTACTACTGCACCCGGTGG ACAACCGGCACAGGCGCTTATTGGGGCCAGGGCACCACAGTGACCGTGTCCTCT SEQ ID NO: 91 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 92 DNA HC GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGC AAGGGCTCTGGCTACACCTTCACCACCTACTGGATGCACTGGGTGCGACAGGCTACCGGCCAGGGC CTGGAATGGATGGGCAACATCTATCCTGGCACCGGCGGCTCCAACTTCGACGAGAAGTTCAAGAAC AGAGTGACCATCACCGCCGACAAGTCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGAGATCC GAGGACACCGCCGTGTACTACTGCACCCGGTGGACAACCGGCACAGGCGCTTATTGGGGCCAGGGC ACCACAGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCC AGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTG ACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGC AGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTAC ACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGC CCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCC AAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCC CAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACC AAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAG GACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAA AAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAA GAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATC GCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGAC AGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAAC GTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTG TCCCTGGGC BAP049-Clone-A LC SEQ ID NO:10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRESSEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33 (Chothia)LCDR3 DYSYPY SEQ ID NO: 42 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 93 DNA VL GAGATCGTGCTGACCCAGTCCCCTGCCACCCTGTCACTGTCTCCAGGCGAGAGAGCTACCCTGTCC TGCAAGTCCTCCCAGTCCCTGCTGGACTCCGGCAACCAGAAGAACTTCCTGACCTGGTATCAGCAG AAGCCCGGCCAGGCCCCCAGACTGCTGATCTACTGGGCCTCCACCCGGGAATCTGGCGTGCCCTCT AGATTCTCCGGCTCCGGCTCTGGCACCGAGTTTACCCTGACCATCTCCAGCCTGCAGCCCGACGAC TTCGCCACCTACTACTGCCAGAACGACTACTCCTACCCCTACACCTTCGGCCAGGGCACCAAGGTG GAAATCAAG SEQ ID NO: 44 LCEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQNDYS YPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 94 DNA LCGAGATCGTGCTGACCCAGTCCCCTGCCACCCTG TCACTGTCTCCAGGCGAGAGAGCTACCCTGTCCTGCAAGTCCTCCCAGTCCCTGCTGGACTCCGGC AACCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC TGGGCCTCCACCCGGGAATCTGGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGGCACCGAGTTT ACCCTGACCATCTCCAGCCTGCAGCCCGACGACTTCGCCACCTACTACTGCCAGAACGACTACTCC TACCCCTACACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAAC AACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTG AGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCBAP049-Clone-B HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat)HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4(Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3(Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VHEVQLVQSGAEVKKPGESLRISCKGSGYTFTTYW MHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 95 DNAVH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTG AAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAGGCTACACCTTCACTACCTACTGG ATGCACTGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACC GGCGGCTCTAACTTCGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGC ACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCACTAGGTGG ACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 91 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 96 DNA HC GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGT AAAGGTTCAGGCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTCAAGGC CTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT AGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCA GAGGACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGC ACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGC CGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTG ACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGC TCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTAC ACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGC CCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCG AAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCA CAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACC AAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAG GACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAA AAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAG GAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATC GCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGAC TCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAAT GTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTC TCCCTGGGA BAP049-Clone-B LC SEQ ID NO:10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRESSEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33 (Chothia)LCDR3 DYSYPY SEQ ID NO: 54 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 97 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGC TGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACCTGGTATCAGCAG AAGCCCGGTAAAGCCCCTAAGCTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCT AGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGCAGCCCGAGGAT ATCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTCGGTCAAGGCACTAAGGTC GAGATTAAG SEQ ID NO: 56 LCEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYS YPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 98 DNA LCGAGATCGTCCTGACTCAGTCACCCGCTACCCTG AGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGT AATCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTAC TGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTC ACCTTCACTATCTCTAGCCTGCAGCCCGAGGATATCGCTACCTACTACTGTCAGAACGACTATAGC TACCCCTACACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAAC AACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTG AGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCBAP049-Clone-C HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat)HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4(Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3(Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VHEVQLVQSGAEVKKPGESLRISCKGSGYTFTTYW MHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 90 DNAVH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTCTGGCTACACCTTCACCACCTACTGG ATGCACTGGGTGCGACAGGCTACCGGCCAGGGCCTGGAATGGATGGGCAACATCTATCCTGGCACC GGCGGCTCCAACTTCGACGAGAAGTTCAAGAACAGAGTGACCATCACCGCCGACAAGTCCACCTCC ACCGCCTACATGGAACTGTCCTCCCTGAGATCCGAGGACACCGCCGTGTACTACTGCACCCGGTGG ACAACCGGCACAGGCGCTTATTGGGGCCAGGGCACCACAGTGACCGTGTCCTCT SEQ ID NO: 91 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 92 DNA HC GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGC AAGGGCTCTGGCTACACCTTCACCACCTACTGGATGCACTGGGTGCGACAGGCTACCGGCCAGGGC CTGGAATGGATGGGCAACATCTATCCTGGCACCGGCGGCTCCAACTTCGACGAGAAGTTCAAGAAC AGAGTGACCATCACCGCCGACAAGTCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGAGATCC GAGGACACCGCCGTGTACTACTGCACCCGGTGGACAACCGGCACAGGCGCTTATTGGGGCCAGGGC ACCACAGTGACCGTGTCCTCTGCTTCTACCAAGGGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCC AGAAGCACCAGCGAGAGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTG ACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGC AGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCAAGACCTAC ACCTGTAACGTGGACCACAAGCCCAGCAACACCAAGGTGGACAAGAGGGTGGAGAGCAAGTACGGC CCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCC AAGCCCAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGACGTGTCC CAGGAGGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACC AAGCCCAGAGAGGAGCAGTTTAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAG GACTGGCTGAACGGCAAAGAGTACAAGTGTAAGGTCTCCAACAAGGGCCTGCCAAGCAGCATCGAA AAGACCATCAGCAAGGCCAAGGGCCAGCCTAGAGAGCCCCAGGTCTACACCCTGCCACCCAGCCAA GAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTACCCAAGCGACATC GCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCCAGTGCTGGAC AGCGACGGCAGCTTCTTCCTGTACAGCAGGCTGACCGTGGACAAGTCCAGATGGCAGGAGGGCAAC GTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTG TCCCTGGGC BAP049-Clone-C LC SEQ ID NO:10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRESSEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33 (Chothia)LCDR3 DYSYPY SEQ ID NO: 66 VL EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 99 DNA VL GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTCCGTGACCCCCAAAGAAAAAGTGACCATCACA TGCAAGTCCTCCCAGTCCCTGCTGGACTCCGGCAACCAGAAGAACTTCCTGACCTGGTATCAGCAG AAGCCCGGCCAGGCCCCCAGACTGCTGATCTACTGGGCCTCCACCCGGGAATCTGGCGTGCCCTCT AGATTCTCCGGCTCCGGCTCTGGCACCGACTTTACCTTCACCATCTCCAGCCTGGAAGCCGAGGAC GCCGCCACCTACTACTGCCAGAACGACTACTCCTACCCCTACACCTTCGGCCAGGGCACCAAGGTG GAAATCAAG SEQ ID NO: 68 LCEIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 100 DNA LCGAGATCGTGCTGACCCAGTCCCCCGACTTCCAG TCCGTGACCCCCAAAGAAAAAGTGACCATCACATGCAAGTCCTCCCAGTCCCTGCTGGACTCCGGC AACCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC TGGGCCTCCACCCGGGAATCTGGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGGCACCGACTTT ACCTTCACCATCTCCAGCCTGGAAGCCGAGGACGCCGCCACCTACTACTGCCAGAACGACTACTCC TACCCCTACACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAAC AACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTG AGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCBAP049-Clone-D HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat)HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4(Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3(Chothia) HCDR3 WTTGTGAY SEQ ID NO: 50 VHEVQLVQSGAEVKKPGESLRISCKGSGYTFTTYW MHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 101 DNAVH GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTCTGGCTACACCTTCACCACCTACTGG ATGCACTGGATCCGGCAGTCCCCCTCTAGGGGCCTGGAATGGCTGGGCAACATCTACCCTGGCACC GGCGGCTCCAACTTCGACGAGAAGTTCAAGAACAGGTTCACCATCTCCCGGGACAACTCCAAGAAC ACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGTACCAGATGG ACCACCGGAACCGGCGCCTATTGGGGCCAGGGCACAACAGTGACCGTGTCCTCC SEQ ID NO: 102 HCEVQLVQSGAEVKKPGESLRISCKGSGYTFTTYW MHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRW TTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTS GVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEF LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLT CLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEAL HNHYTQKSLSLSLG SEQ ID NO: 103 DNA HCGAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTG AAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTCTGGCTACACCTTCACCACCTACTGG ATGCACTGGATCCGGCAGTCCCCCTCTAGGGGCCTGGAATGGCTGGGCAACATCTACCCTGGCACC GGCGGCTCCAACTTCGACGAGAAGTTCAAGAACAGGTTCACCATCTCCCGGGACAACTCCAAGAAC ACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCGCCGTGTACTACTGTACCAGATGG ACCACCGGAACCGGCGCCTATTGGGGCCAGGGCACAACAGTGACCGTGTCCTCCGCTTCTACCAAG GGGCCCAGCGTGTTCCCCCTGGCCCCCTGCTCCAGAAGCACCAGCGAGAGCACAGCCGCCCTGGGC TGCCTGGTGAAGGACTACTTCCCCGAGCCCGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGC GGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACC GTGCCCAGCAGCAGCCTGGGCACCAAGACCTACACCTGTAACGTGGACCACAAGCCCAGCAACACC AAGGTGGACAAGAGGGTGGAGAGCAAGTACGGCCCACCCTGCCCCCCCTGCCCAGCCCCCGAGTTC CTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCCAAGCCCAAGGACACCCTGATGATCAGCAGAACC CCCGAGGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCAACTGGTAC GTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTTTAACAGCACCTAC CGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAGTACAAGTGTAAG GTCTCCAACAAGGGCCTGCCAAGCAGCATCGAAAAGACCATCAGCAAGGCCAAGGGCCAGCCTAGA GAGCCCCAGGTCTACACCCTGCCACCCAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACC TGTCTGGTGAAGGGCTTCTACCCAAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAGGCTG ACCGTGGACAAGTCCAGATGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTG CACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGC BAP049-Clone-D LC SEQ ID NO: 10 (Kabat) LCDR1KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRES SEQ ID NO: 32(Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1 SQSLLDSGNQKNF SEQID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33 (Chothia) LCDR3 DYSYPY SEQID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 104 DNA VL GAGATCGTGCTGACCCAGTCCCCTGCCACCCTGTCACTGTCTCCAGGCGAGAGAGCTACCCTGTCC TGCAAGTCCTCCCAGTCCCTGCTGGACTCCGGCAACCAGAAGAACTTCCTGACCTGGTATCAGCAG AAGCCCGGCCAGGCCCCCAGACTGCTGATCTACTGGGCCTCCACCCGGGAATCTGGCGTGCCCTCT AGATTCTCCGGCTCCGGCTCTGGCACCGACTTTACCTTCACCATCTCCAGCCTGGAAGCCGAGGAC GCCGCCACCTACTACTGCCAGAACGACTACTCCTACCCCTACACCTTCGGCCAGGGCACCAAGGTG GAAATCAAG SEQ ID NO: 72 LCEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 105 DNA LCGAGATCGTGCTGACCCAGTCCCCTGCCACCCTG TCACTGTCTCCAGGCGAGAGAGCTACCCTGTCCTGCAAGTCCTCCCAGTCCCTGCTGGACTCCGGC AACCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCTGATCTAC TGGGCCTCCACCCGGGAATCTGGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGGCACCGACTTT ACCTTCACCATCTCCAGCCTGGAAGCCGAGGACGCCGCCACCTACTACTGCCAGAACGACTACTCC TACCCCTACACCTTCGGCCAGGGCACCAAGGTGGAAATCAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCAAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAAC AACTTCTACCCCAGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTG AGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCBAP049-Clone-E HC SEQ ID NO: 1 (Kabat) HCDR1 TYWMH SEQ ID NO: 2 (Kabat)HCDR2 NIYPGTGGSNFDEKFKN SEQ ID NO: 3 (Kabat) HCDR3 WTTGTGAY SEQ ID NO: 4(Chothia) HCDR1 GYTFTTY SEQ ID NO: 5 (Chothia) HCDR2 YPGTGG SEQ ID NO: 3(Chothia) HCDR3 WTTGTGAY SEQ ID NO: 38 VHEVQLVQSGAEVKKPGESLRISCKGSGYTFTTYW MHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRW TTGTGAYWGQGTTVTVSS SEQ ID NO: 95 DNAVH GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTG AAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCAGGCTACACCTTCACTACCTACTGG ATGCACTGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGATGGGTAATATCTACCCCGGCACC GGCGGCTCTAACTTCGACGAGAAGTTTAAGAATAGAGTGACTATCACCGCCGATAAGTCTACTAGC ACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCGCCGTCTACTACTGCACTAGGTGG ACTACCGGCACAGGCGCCTACTGGGGTCAAGGCACTACCGTGACCGTGTCTAGC SEQ ID NO: 91 HC EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKN RVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSSASTKGPSVFPLAPCS RSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTY TCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVS QEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD SDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG SEQ ID NO: 96 DNA HC GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGT AAAGGTTCAGGCTACACCTTCACTACCTACTGGATGCACTGGGTCCGCCAGGCTACCGGTCAAGGC CTCGAGTGGATGGGTAATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT AGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCA GAGGACACCGCCGTCTACTACTGCACTAGGTGGACTACCGGCACAGGCGCCTACTGGGGTCAAGGC ACTACCGTGACCGTGTCTAGCGCTAGCACTAAGGGCCCGTCCGTGTTCCCCCTGGCACCTTGTAGC CGGAGCACTAGCGAATCCACCGCTGCCCTCGGCTGCCTGGTCAAGGATTACTTCCCGGAGCCCGTG ACCGTGTCCTGGAACAGCGGAGCCCTGACCTCCGGAGTGCACACCTTCCCCGCTGTGCTGCAGAGC TCCGGGCTGTACTCGCTGTCGTCGGTGGTCACGGTGCCTTCATCTAGCCTGGGTACCAAGACCTAC ACTTGCAACGTGGACCACAAGCCTTCCAACACTAAGGTGGACAAGCGCGTCGAATCGAAGTACGGC CCACCGTGCCCGCCTTGTCCCGCGCCGGAGTTCCTCGGCGGTCCCTCGGTCTTTCTGTTCCCACCG AAGCCCAAGGACACTTTGATGATTTCCCGCACCCCTGAAGTGACATGCGTGGTCGTGGACGTGTCA CAGGAAGATCCGGAGGTGCAGTTCAATTGGTACGTGGATGGCGTCGAGGTGCACAACGCCAAAACC AAGCCGAGGGAGGAGCAGTTCAACTCCACTTACCGCGTCGTGTCCGTGCTGACGGTGCTGCATCAG GACTGGCTGAACGGGAAGGAGTACAAGTGCAAAGTGTCCAACAAGGGACTTCCTAGCTCAATCGAA AAGACCATCTCGAAAGCCAAGGGACAGCCCCGGGAACCCCAAGTGTATACCCTGCCACCGAGCCAG GAAGAAATGACTAAGAACCAAGTCTCATTGACTTGCCTTGTGAAGGGCTTCTACCCATCGGATATC GCCGTGGAATGGGAGTCCAACGGCCAGCCGGAAAACAACTACAAGACCACCCCTCCGGTGCTGGAC TCAGACGGATCCTTCTTCCTCTACTCGCGGCTGACCGTGGATAAGAGCAGATGGCAGGAGGGAAAT GTGTTCAGCTGTTCTGTGATGCATGAAGCCCTGCACAACCACTACACTCAGAAGTCCCTGTCCCTC TCCCTGGGA BAP049-Clone-E LC SEQ ID NO:10 (Kabat) LCDR1 KSSQSLLDSGNQKNFLT SEQ ID NO: 11 (Kabat) LCDR2 WASTRESSEQ ID NO: 32 (Kabat) LCDR3 QNDYSYPYT SEQ ID NO: 13 (Chothia) LCDR1SQSLLDSGNQKNF SEQ ID NO: 14 (Chothia) LCDR2 WAS SEQ ID NO: 33 (Chothia)LCDR3 DYSYPY SEQ ID NO: 70 VL EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPS RFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK SEQ ID NO: 106 DNA VL GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGC TGTAAATCTAGTCAGTCACTGCTGGATAGCGGTAATCAGAAGAACTTCCTGACCTGGTATCAGCAG AAGCCCGGTCAAGCCCCTAGACTGCTGATCTACTGGGCCTCTACTAGAGAATCAGGCGTGCCCTCT AGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGGAAGCCGAGGAC GCCGCTACCTACTACTGTCAGAACGACTATAGCTACCCCTACACCTTCGGTCAAGGCACTAAGGTC GAGATTAAG SEQ ID NO: 72 LCEIVLTQSPATLSLSPGERATLSCKSSQSLLDSG NQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYS YPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 107 DNA LCGAGATCGTCCTGACTCAGTCACCCGCTACCCTG AGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGTAAATCTAGTCAGTCACTGCTGGATAGCGGT AATCAGAAGAACTTCCTGACCTGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACTGCTGATCTAC TGGGCCTCTACTAGAGAATCAGGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTC ACCTTCACTATCTCTAGCCTGGAAGCCGAGGACGCCGCTACCTACTACTGTCAGAACGACTATAGC TACCCCTACACCTTCGGTCAAGGCACTAAGGTCGAGATTAAGCGTACGGTGGCCGCTCCCAGCGTG TTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTGCTGAAC AACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAACGCCCTGCAGAGCGGCAACAGC CAGGAGAGCGTCACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTG AGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAGGTGACCCACCAGGGCCTGTCCAGC CCCGTGACCAAGAGCTTCAACAGGGGCGAGTGCBAP049 HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109(Kabat) HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQID NO: 110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111(Chothia) HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 115 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTGCACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 118 (Chothia) LCDR3 GATTATAGTTATCCGTGC BAP049-chiHC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-chi LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 115 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTGCACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 118 (Chothia) LCDR3 GATTATAGTTATCCGTGC BAP049-chi YHC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-chi Y LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum01HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum01 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum02HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum02 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum03HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum03 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum04HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum04 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum05HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum05 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum06HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum06 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum07HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum07 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum08HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum08 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum09HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum09 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum10HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum10 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum11HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum11 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum12HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum12 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum13HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum13 LC SEQ ID NO: 121 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTAACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum14HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:223 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAC SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 223 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAC BAP049-hum14 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum15HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:223 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAC SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 223 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAC BAP049-hum15 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTAC BAP049-hum16HC SEQ ID NO: 108 (Kabat) HCDR1 ACTTACTGGATGCAC SEQ ID NO: 109 (Kabat)HCDR2 AATATTTATCCTGGTACTGGTGGTTCTAACTTC GATGAGAAGTTCAAGAAC SEQ ID NO:110 (Kabat) HCDR3 TGGACTACTGGGACGGGAGCTTAT SEQ ID NO: 111 (Chothia)HCDR1 GGCTACACATTCACCACTTAC SEQ ID NO: 112 (Chothia) HCDR2TATCCTGGTACTGGTGGT SEQ ID NO: 110 (Chothia) HCDR3TGGACTACTGGGACGGGAGCTTAT BAP049-hum16 LC SEQ ID NO: 113 (Kabat) LCDR1AAGTCCAGTCAGAGTCTGTTAGACAGTGGAAAT CAAAAGAACTTCTTGACC SEQ ID NO: 114(Kabat) LCDR2 TGGGCATCCACTAGGGAATCT SEQ ID NO: 119 (Kabat) LCDR3CAGAATGATTATAGTTATCCGTACACG SEQ ID NO: 116 (Chothia) LCDR1AGTCAGAGTCTGTTAGACAGTGGAAATCAAAAG AACTTC SEQ ID NO: 117 (Chothia) LCDR2TGGGCATCC SEQ ID NO: 120 (Chothia) LCDR3 GATTATAGTTATCCGTACBAP049-Clone-A HC SEQ ID NO: 122 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ IDNO: 123 (Kabat) HCDR2 AACATCTATCCTGGCACCGGCGGCTCCAACTTCGACGAGAAGTTCAAGAAC SEQ ID NO: 124 (Kabat) HCDR3 TGGACAACCGGCACAGGCGCTTATSEQ ID NO: 125 (Chothia) HCDR1 GGCTACACCTTCACCACCTAC SEQ ID NO: 126(Chothia) HCDR2 TATCCTGGCACCGGCGGC SEQ ID NO: 124 (Chothia) HCDR3TGGACAACCGGCACAGGCGCTTAT BAP049-Clone-A LC SEQ ID NO: 127 (Kabat) LCDR1AAGTCCTCCCAGTCCCTGCTGGACTCCGGCAAC CAGAAGAACTTCCTGACC SEQ ID NO: 128(Kabat) LCDR2 TGGGCCTCCACCCGGGAATCT SEQ ID NO: 129 (Kabat) LCDR3CAGAACGACTACTCCTACCCCTACACC SEQ ID NO: 130 (Chothia) LCDR1TCCCAGTCCCTGCTGGACTCCGGCAACCAGAAG AACTTC SEQ ID NO: 131 (Chothia) LCDR2TGGGCCTCC SEQ ID NO: 132 (Chothia) LCDR3 GACTACTCCTACCCCTACBAP049-Clone-B HC SEQ ID NO: 133 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ IDNO: 134 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 135 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTACSEQ ID NO: 136 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 137(Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 135 (Chothia) HCDR3TGGACTACCGGCACAGGCGCCTAC BAP049-Clone-B LC SEQ ID NO: 138 (Kabat) LCDR1AAATCTAGTCAGTCACTGCTGGATAGCGGTAAT CAGAAGAACTTCCTGACC SEQ ID NO: 139(Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 140 (Kabat) LCDR3CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 141 (Chothia) LCDR1AGTCAGTCACTGCTGGATAGCGGTAATCAGAAG AACTTC SEQ ID NO: 142 (Chothia) LCDR2TGGGCCTCT SEQ ID NO: 143 (Chothia) LCDR3 GACTATAGCTACCCCTACBAP049-Clone-C HC SEQ ID NO: 122 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ IDNO: 123 (Kabat) HCDR2 AACATCTATCCTGGCACCGGCGGCTCCAACTTCGACGAGAAGTTCAAGAAC SEQ ID NO: 124 (Kabat) HCDR3 TGGACAACCGGCACAGGCGCTTATSEQ ID NO: 125 (Chothia) HCDR1 GGCTACACCTTCACCACCTAC SEQ ID NO: 126(Chothia) HCDR2 TATCCTGGCACCGGCGGC SEQ ID NO: 124 (Chothia) HCDR3TGGACAACCGGCACAGGCGCTTAT BAP049-Clone-C LC SEQ ID NO: 127 (Kabat) LCDR1AAGTCCTCCCAGTCCCTGCTGGACTCCGGCAAC CAGAAGAACTTCCTGACC SEQ ID NO: 128(Kabat) LCDR2 TGGGCCTCCACCCGGGAATCT SEQ ID NO: 129 (Kabat) LCDR3CAGAACGACTACTCCTACCCCTACACC SEQ ID NO: 130 (Chothia) LCDR1TCCCAGTCCCTGCTGGACTCCGGCAACCAGAAG AACTTC SEQ ID NO: 131 (Chothia) LCDR2TGGGCCTCC SEQ ID NO: 132 (Chothia) LCDR3 GACTACTCCTACCCCTACBAP049-Clone-D HC SEQ ID NO: 122 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ IDNO: 144 (Kabat) HCDR2 AACATCTACCCTGGCACCGGCGGCTCCAACTTCGACGAGAAGTTCAAGAAC SEQ ID NO: 145 (Kabat) HCDR3 TGGACCACCGGAACCGGCGCCTATSEQ ID NO: 125 (Chothia) HCDR1 GGCTACACCTTCACCACCTAC SEQ ID NO: 146(Chothia) HCDR2 TACCCTGGCACCGGCGGC SEQ ID NO: 145 (Chothia) HCDR3TGGACCACCGGAACCGGCGCCTAT BAP049-Clone-D LC SEQ ID NO: 127 (Kabat) LCDR1AAGTCCTCCCAGTCCCTGCTGGACTCCGGCAAC CAGAAGAACTTCCTGACC SEQ ID NO: 128(Kabat) LCDR2 TGGGCCTCCACCCGGGAATCT SEQ ID NO: 129 (Kabat) LCDR3CAGAACGACTACTCCTACCCCTACACC SEQ ID NO: 130 (Chothia) LCDR1TCCCAGTCCCTGCTGGACTCCGGCAACCAGAAG AACTTC SEQ ID NO: 131 (Chothia) LCDR2TGGGCCTCC SEQ ID NO: 132 (Chothia) LCDR3 GACTACTCCTACCCCTACBAP049-Clone-E HC SEQ ID NO: 133 (Kabat) HCDR1 ACCTACTGGATGCAC SEQ IDNO: 134 (Kabat) HCDR2 AATATCTACCCCGGCACCGGCGGCTCTAACTTCGACGAGAAGTTTAAGAAT SEQ ID NO: 135 (Kabat) HCDR3 TGGACTACCGGCACAGGCGCCTACSEQ ID NO: 136 (Chothia) HCDR1 GGCTACACCTTCACTACCTAC SEQ ID NO: 137(Chothia) HCDR2 TACCCCGGCACCGGCGGC SEQ ID NO: 135 (Chothia) HCDR3TGGACTACCGGCACAGGCGCCTAC BAP049-Clone-E LC SEQ ID NO: 138 (Kabat) LCDR1AAATCTAGTCAGTCACTGCTGGATAGCGGTAAT CAGAAGAACTTCCTGACC SEQ ID NO: 139(Kabat) LCDR2 TGGGCCTCTACTAGAGAATCA SEQ ID NO: 140 (Kabat) LCDR3CAGAACGACTATAGCTACCCCTACACC SEQ ID NO: 141 (Chothia) LCDR1AGTCAGTCACTGCTGGATAGCGGTAATCAGAAG AACTTC SEQ ID NO: 142 (Chothia) LCDR2TGGGCCTCT SEQ ID NO: 143 (Chothia) LCDR3 GACTATAGCTACCCCTAC

TABLE 2 Amino acid and nucleotide sequences of the heavy and light chainframework regions for humanized mAbs BAP049-hum01 to BAP049-hum16 andBAP049-Clone-A to BAP049-Clone-E Amino Acid Sequence Nucleotide SequenceVHFW1 EVQLVQSGAEVKKPGESLRISCKGS GAAGTGCAGCTGGTGCAGTCTGGAGCAGAGGTGAAAAA(type a) (SEQ ID NO: 147) GCCCGGGGAGTCTCTGAGGATCTCCTGTAAGGGTTCT (SEQ IDNO: 148) GAAGTGCAGCTGGTGCAGTCTGGCGCCGAAGTGAAGAAGCCTGGCGAGTCCCTGCGGATCTCCTGCAAGGGCTCT (SEQ ID NO: 149)GAGGTGCAGCTGGTGCAGTCAGGCGCCGAAGTGAAGAAGCCCGGCGAGTCACTGAGAATTAGCTGTAAAGGTTCA (SEQ ID NO: 150) VHFW1QVQLVQSGAEVKKPGASVKVSCKAS CAGGTTCAGCTGGTGCAGTCTGGAGCTGAGGTGAAGAA (typeb) (SEQ ID NO: 151) GCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTTCT (SEQ ID NO:152) VHFW2 WVRQATGQGLEWMG TGGGTGCGACAGGCCACTGGACAAGGGCTTGAGTGGAT (typea) (SEQ ID NO: 153) GGGT (SEQ ID NO: 154)TGGGTGCGACAGGCTACCGGCCAGGGCCTGGAATGGAT GGGC (SEQ ID NO: 155)TGGGTCCGCCAGGCTACCGGTCAAGGCCTCGAGTGGAT GGGT (SEQ ID NO: 156) VHFW2WIRQSPSRGLEWLG TGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCT (type b) (SEQ IDNO: 157) GGGT (SEQ ID NO: 158) TGGATCCGGCAGTCCCCCTCTAGGGGCCTGGAATGGCTGGGC (SEQ ID NO: 159) VHFW2 WVRQAPGQGLEWMGTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGAT (type c) (SEQ ID NO: 160) GGGT(SEQ ID NO: 161) VHFW3 RVTITADKSTSTAYMELSSLRSEDTAVYAGAGTCACGATTACCGCGGACAAATCCACGAGCACAGC (type a) YCTR (SEQ ID NO: 162)CTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGG CCGTGTATTACTGTACAAGA (SEQ ID NO:163) AGAGTGACCATCACCGCCGACAAGTCCACCTCCACCGCCTACATGGAACTGTCCTCCCTGAGATCCGAGGACACCG CCGTGTACTACTGCACCCGG (SEQ ID NO:164) AGAGTGACTATCACCGCCGATAAGTCTACTAGCACCGCCTATATGGAACTGTCTAGCCTGAGATCAGAGGACACCG CCGTCTACTACTGCACTAGG (SEQ ID NO:165) VHFW3 RFTISRDNSKNTLYLQMNSLRAEDTAVYAGATTCACCATCTCCAGAGACAATTCCAAGAACACGCT (type b) YCTR (SEQ ID NO: 166)GTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGG CCGTGTATTACTGTACAAGA (SEQ ID NO:167) AGGTTCACCATCTCCCGGGACAACTCCAAGAACACCCTGTACCTGCAGATGAACTCCCTGCGGGCCGAGGACACCG CCGTGTACTACTGTACCAGA (SEQ ID NO:168) VHFW4 WGQGTTVTVSS TGGGGCCAGGGCACCACCGTGACCGTGTCCTCC (SEQ (SEQ IDNO: 169) ID NO: 170) TGGGGCCAGGGCACCACAGTGACCGTGTCCTCT (SEQ ID NO: 171)TGGGGTCAAGGCACTACCGTGACCGTGTCTAGC (SEQ ID NO: 172)TGGGGCCAGGGCACAACAGTGACCGTGTCCTCC (SEQ ID NO: 173) VLFW1EIVLTQSPDFQSVTPKEKVTITC (SEQ GAAATTGTGCTGACTCAGTCTCCAGACTTTCAGTCTGT(type a) ID NO: 174) GACTCCAAAGGAGAAAGTCACCATCACCTGC (SEQ ID NO: 175)GAGATCGTGCTGACCCAGTCCCCCGACTTCCAGTCCGT GACCCCCAAAGAAAAAGTGACCATCACATGC(SEQ ID NO: 176) VLFW1 EIVLTQSPATLSLSPGERATLSCGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTT (type b) (SEQ ID NO: 177)GTCTCCAGGGGAAAGAGCCACCCTCTCCTGC (SEQ ID NO: 178)GAGATCGTGCTGACCCAGTCCCCTGCCACCCTGTCACT GTCTCCAGGCGAGAGAGCTACCCTGTCCTGC(SEQ ID NO: 179) GAGATCGTCCTGACTCAGTCACCCGCTACCCTGAGCCTGAGCCCTGGCGAGCGGGCTACACTGAGCTGT (SEQ ID NO: 180) VLFW1DIVMTQTPLSLPVTPGEPASISC (SEQ GATATTGTGATGACCCAGACTCCACTCTCCCTGCCCGT(type c) ID NO: 181) CACCCCTGGAGAGCCGGCCTCCATCTCCTGC (SEQ ID NO: 182)VLFW1 DVVMTQSPLSLPVTLGQPASISC (SEQGATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGT (type d) ID NO: 183)CACCCTTGGACAGCCGGCCTCCATCTCCTGC (SEQ ID NO: 184) VLFW1DIQMTQSPSSLSASVGDRVTITC (SEQ GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGC(type e) ID NO: 185) ATCTGTAGGAGACAGAGTCACCATCACTTGC (SEQ ID NO: 186)VLFW2 WYQQKPGQAPRLLIY TGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCT (type a)(SEQ ID NO: 187) CATCTAT (SEQ ID NO: 188)TGGTATCAGCAGAAGCCCGGCCAGGCCCCCAGACTGCT GATCTAC (SEQ ID NO: 189)TGGTATCAGCAGAAGCCCGGTCAAGCCCCTAGACTGCT GATCTAC (SEQ ID NO: 190) VLFW2WYQQKPGKAPKLLIY TGGTATCAGCAGAAACCAGGGAAAGCTCCTAAGCTCCT (type b) (SEQ IDNO: 191) GATCTAT (SEQ ID NO: 192) TGGTATCAGCAGAAGCCCGGTAAAGCCCCTAAGCTGCTGATCTAC (SEQ ID NO: 193) VLFW2 WYLQKPGQSPQLLIYTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCT (type c) (SEQ ID NO: 194) GATCTAT(SEQ ID NO: 195) VLFW3 GVPSRFSGSGSGTDFTFTISSLEAEDAAGGGGTCCCCTCGAGGTTCAGTGGCAGTGGATCTGGGAC (type a) TYYC (SEQ ID NO: 196)AGATTTCACCTTTACCATCAGTAGCCTGGAAGCTGAAG ATGCTGCAACATATTACTGT (SEQ ID NO:197) GGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGGCACCGACTTTACCTTCACCATCTCCAGCCTGGAAGCCGAGG ACGCCGCCACCTACTACTGC (SEQ ID NO:198) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGGAAGCCGAGG ACGCCGCTACCTACTACTGT (SEQ ID NO:199) VLFW3 GIPPRFSGSGYGTDFTLTINNIESEDAAGGGATCCCACCTCGATTCAGTGGCAGCGGGTATGGAAC (type b) YYFC (SEQ ID NO: 200)AGATTTTACCCTCACAATTAATAACATAGAATCTGAGG ATGCTGCATATTACTTCTGT (SEQ ID NO:201) VLFW3 GVPSRFSGSGSGTEFTLTISSLQPDDFAGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGAC (type c) TYYC (SEQ ID NO: 202)AGAATTCACTCTCACCATCAGCAGCCTGCAGCCTGATG ATTTTGCAACTTATTACTGT (SEQ ID NO:203) GGCGTGCCCTCTAGATTCTCCGGCTCCGGCTCTGGCACCGAGTTTACCCTGACCATCTCCAGCCTGCAGCCCGACG ACTTCGCCACCTACTACTGC (SEQ ID NO:204) VLFW3 GVPSRFSGSGSGTDFTFTISSLQPEDIAGGGGTCCCATCAAGGTTCAGTGGAAGTGGATCTGGGAC (type d) TYYC (SEQ ID NO: 205)AGATTTTACTTTCACCATCAGCAGCCTGCAGCCTGAAG ATATTGCAACATATTACTGT (SEQ ID NO:206) GGCGTGCCCTCTAGGTTTAGCGGTAGCGGTAGTGGCACCGACTTCACCTTCACTATCTCTAGCCTGCAGCCCGAGG ATATCGCTACCTACTACTGT (SEQ ID NO:207) VLFW4 FGQGTKVEIK (SEQ ID NO: 208) TTCGGCCAAGGGACCAAGGTGGAAATCAAA(SEQ ID NO: 209) TTCGGCCAGGGCACCAAGGTGGAAATCAAG (SEQ ID NO: 210)TTCGGTCAAGGCACTAAGGTCGAGATTAAG (SEQ ID NO: 211)

TABLE 3 Constant region amino acid sequences of human IgG heavy chainsand human kappa light chain HC IgG4 (S228P) mutant constant region aminoacid sequence (EU Numbering) ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVSWNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVESKYGPPCPPCP APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSQED PEVQFNWYVDGVEVHNAKTK PREEQFNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAKGQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDSDGSFFLYSRL TVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLGK (SEQ ID NO: 212) LCHuman kappa constant region amino acid sequence RTVAAPSVFI FPPSDEQLKSGTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYEKHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO: 213) HC IgG4 (S228P) mutantconstant region amino acid sequence lacing C-terminal lysine (K) (EUNumbering) ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSSLGTKT YTCNVDHKPS NTKVDKRVES KYGPPCPPCPAPEFLGGPSV FLFPPKPKDT LMISRTPEVT CVVVDVSQED PEVQFNWYVD GVEVHNAKTKPREEQFNSTY RVVSVLTVLH QDWLNGKEYK CKVSNKGLPS SIEKTISKAK GQPREPQVYTLPPSQEEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSRLTVDKSRWQEG NVFSCSVMHE ALHNHYTQKS LSLSLG (SEQ ID NO: 214) HC IgG1 wildtype ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSSLGTQT YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGGPSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYNSTYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREEMTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRWQQGNVFSCSV MHEALHNHYT QKSLSLSPGK (SEQ ID NO: 215) HC IgG1 (N297A) mutantconstant region amino acid sequence (EU Numbering) ASTKGPSVFP LAPSSKSTSGGTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQTYICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTPEVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYA STYRVVSVLT VLHQDWLNGKEYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDIAVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 216) HC IgG1 (D265A, P329A) mutant constantregion amino acid sequence (EU Numbering) ASTKGPSVFP LAPSSKSTSGGTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQTYICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP KDTLMISRTPEVTCVVVAVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGKEYKCKVSNKA LAAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDIAVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 217) HC IgG1 (L234A, L235A) mutant constantregion amino acid sequence (EU Numbering) ASTKGPSVFP LAPSSKSTSGGTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQTYICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPEAAGG PSVFLFPPKP KDTLMISRTPEVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN STYRVVSVLT VLHQDWLNGKEYKCKVSNKA LPAPIEKTIS KAKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDIAVEWESNGQP ENNYKTTPPV LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYTQKSLSLSPGK (SEQ ID NO: 218)

TABLE 4 Amino acid sequences of the heavy and light chain leadersequences for humanized mAbs BAP049- Clone-A to BAP049-Clone-E BAP049-HC MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 219) Clone-A LC MSVPTQVLGLLLLWLTDARC(SEQ ID NO: 220) BAP049- HC MAWVWTLPFLMAAAQSVQA (SEQ ID NO: 221) Clone-BLC MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 222) BAP049- HC MEWSWVFLFFLSVTTGVHS(SEQ ID NO: 219) Clone-C LC MSVPTQVLGLLLLWLTDARC (SEQ ID NO: 220)BAP049- HC MEWSWVFLFFLSVTTGVHS (SEQ ID NO: 219) Clone-D LCMSVPTQVLGLLLLWLTDARC (SEQ ID NO: 220) BAP049- HC MAWVWTLPFLMAAAQSVQA(SEQ ID NO: 221) Clone-E LC MSVLTQVLALLLLWLTGTRC (SEQ ID NO: 222)

Table 5. See Examples.

Table 6. See Examples.

TABLE 7 Selected therapeutic agents that can be administered incombination with the anti-PD-1 antibody molecules, e.g., as a singleagent or in combination with other immunomodulators described herein.Each publication listed in this Table is herein incorporated byreference in its entirety, including all structural formulae therein.Patents/Patent Compound Generic Name Application Designation TradenameCompound Structure Publications A1  Sotrastaurin

EP 1682103 US 2007/142401 WO 2005/039549 A2  Nilotinib HCl monohydratcTASIGNA ®

WO 2004/005281 U.S. Pat. No. 7,169,791 A3 

WO 2010/060937 WO 2004/072051 EP 1611112 U.S. Pat. No. 8,450,310 A4 Dactolisib

WO 2006/122806 A5 

U.S. Pat. No. 8,552,002 A6  Buparlisib

WO 2007/084786 A7 

WO 2009/141386 US 2010/0105667 A8 

WO 2010/029082 A9  CYP17 inhibitor WO 2010/149755 U.S. Pat. No.8,263,635 B2 EP 2445903 B1 A10

WO 2011/076786 A11 Deferasirox EXJADE ®

WO 1997/049395 A12 Letrozole FEMARA ®

U.S. Pat. No. 4,978,672 A13

WO 2013/124826 US 2013/0225574 A14

WO 2013/111105 A15

WO 2005/073224 A16 Imatinib mesylate GLEEVEC ®

  Mesylate WO 1999/003854 A17

  Dihydrochloric salt EP 2099447 U.S. Pat. No. 7,767,675 U.S. Pat. No.8,420,645 A18 Ruxolitinib Phosphate JAKAFI ®

WO 2007/070514 EP 2474545 U.S. Pat. No. 7,598,257 WO 2014/018632 A19Panobinostat

WO 2014/072493 WO 2002/022577 EP 1870399 A20 Osilodrostat

WO 2007/024945 A21

WO 2008/016893 EP 2051990 U.S. Pat. No. 8,546,336 A22 Sonidegibphosphate

WO 2007/131201 EP 2021328 U.S. Pat. No. 8,178,563 A23 ceritinibZYKADIA ™

WO 2008/073687 U.S. Pat. No. 8,039,479 A24

U.S. Pat. No. 8,415,355 U.S. Pat. No. 8,685,980 A25

WO 2010/007120 A26 Human monoclonal antibody to PRLR U.S. Pat. No.7,867,493 A27

WO 2010/026124 EP 2344474 US 2010/0056576 WO2008/106692 A28

WO 2010/101849 A29 Encorafenib

WO 2011/025927 A30

WO 2011/101409 A31 Human monoclonal antibody to HER3 WO 2012/022814 EP2606070 U.S. Pat. No. 8,735,551 A32 Antibody Drug Conjugate (ADC) WO2014/160160 Ab: 12425 (see Table 1, paragraph [00191]) Linker: SMCC (seeparagraph [00117] Payload: DM1 (see paragraph [00111] See also Claim 29A33 Monoclonal antibody or Fab to M-CSF WO 2004/045532 A34 Binimetinib

WO 2003/077914 A35 Midostaurin

WO 2003/037347 EP 1441737 US 2012/252785 A36 Everolimus AFINITOR ®

WO 2014/085318 A37

WO 2007/030377 U.S. Pat. No. 7,482,367 A38 Pasireotide diaspartateSIGNIFOR ®

WO2002/010192 U.S. Pat. No. 7,473,761 A39 Dovitinib

WO 2009/115562 U.S. Pat. No. 8,563,556 A40

WO 2013/184757 A41

WO 2006/122806 A42

WO 2008/073687 U.S. Pat. No. 8,372,858 A43

WO 2010/002655 U.S. Pat. No. 8,519,129 A44

WO 2010/002655 U.S. Pat. No. 8,519,129 A45

WO 2010/002655 A46 Valspodar AMDRAY ™

EP 296122 A47 Vatalanib succinate

  succinate WO 98/35958 A48 IDH inhibitor WO2014/141104 A49 BCR-ABLinhibitor WO2013/171639 WO2013/171640 WO2013/171641 WO2013/171642 A50cRAF inhibitor WO2014/151616 A51 ERK1/2 ATP competitive inhibitorPCT/US2014/062913

EXAMPLES

The Examples below are set forth to aid in the understanding of theinventions but are not intended to, and should not be construed to,limit its scope in any way.

Example 1: Humanization of Anti-PD-1 Antibody, BAP049

Murine anti-PD-1 monoclonal antibody BAP049 was humanized. The sequencesand test samples of sixteen humanized BAP049 clones with unique variableregion sequences were obtained. These clones were further analyzed fortheir biological functions (e.g., antigen binding and ligand blocking),structural features, and transcient expression in CHO cells.

Example 1.1: Humanization Technology and Process

Humanization of BAP049 was performed using a combinatorial library ofhuman germline variable region frameworks (FWs). The technology entailstransferring the murine CDRs in frame to a library of human variableregions (VRs) that had been constructed by randomly combining human germline FW1, FW2 and FW3 sequences. Only one FW4 sequence was used, whichis WGQGTTVTVSS (SEQ ID NO: 169) for the heavy chain (HC) (Kabat human HCsubgroup I, No. 21) and FGQGTKVEIK (SEQ ID NO: 208) for the light chain(LC) (Kabat human κ subgroup I, No. 5). The library of VR sequences wasfused to human constant region (CR) sequences, human IgG4(S228P) of HCand human κ CR of LC, and the resulting library of whole IgG wasexpressed in CHO cells for screening. Screening was performed withtissue culture supernatants measuring binding avidity onantigen-expressing cells in a whole cell ELISA format or on FACS.

The humanization process was performed in a stepwise manner startingwith the construction and expression of the appropriate chimeric mAb(murine VR, IgG4(S228P), human κ), which can serve as a comparator forthe screening of the humanized clones. The constant region amino acidsequences for human IgG4(S228P) heavy chain and human kappa light chainare shown in Table 3.

Humanization of the VR of LC and HC were performed in two independentsteps. The library of humanized LC (huLC) was paired with the chimericHC (murine VR, IgG4(S228P)) and the resulting “half-humanized” mAbs werescreened for binding activity by ELISA. The huLC of clones with adequatebinding activity (≥binding of chimeric mAb) were selected. Analogously,the library of humanized HC (huHC) was paired with the chimeric LC(murine VR, human κ) and screened for binding activity by ELISA. ThehuHC of clones with appropriate binding activity (≥binding of chimericmAb) were selected.

The variable regions of the selected huLC and huHC were then sequencedto identify the huLC and huHC with unique sequences (some clones fromthe initial selection process may share the same LC or HC). The uniquehuLC and huHC were then randomly combined to form a small library ofhumanized mAbs (humAbs), which was expressed in CHO cells and screenedon antigen-expressing cells in an ELISA and FACS format. Clones withbinding activities that were equal or better than the binding of thechimeric comparator mAb are the final product of the humanizationprocess.

Example 1.2: Sequence of Murine mAb BAP049

The LC and HC variable region sequences of murine anti-PD-1 mAb weredetermined. The sequences obtained from two independent analyses wereidentical and are shown in FIG. 1.

Germline analysis was performed and part of the result is shown in FIG.2A as an amino acid sequence alignment. For the light chain, the V-geneis 98.65% identical to mIGKV8-19*01F (293/297 nts) and the J-gene is97.30% identical to mIGKJ2*01F (36/37 nts). For the heavy chain, theV-gene is 92.83% identical to mIGHV1S22*01F (259/279 nts), the J-gene is82.98% identical to mIGHJ3*01F (39/47 nts), and the D-gene ismIGHD2-14*01F. As shown in FIG. 2B, the LC sequence of the murine mAbcontains an unpaired Cys at position 102, which is in CDRL3 and arosethrough a point mutation in the murine J2 gene (tac→tgc; Y→C).

Example 1.3: Construction of Chimeric Antibody

Three variants of the chimeric antibody were prepared that either had aCys, Tyr or Ser residue at position 102 of the LC sequence. The threechimeric antibodies, i.e., BAP049-chi (Cys), BAP049-chi (Tyr), andBAP049-chi (Ser) (also known as BAP049-chi, BAP049-chi-Y, andBAP049-chi-S, respectively), were expressed in CHO cells and tested fortheir ability to compete with labeled murine antibody for binding toPD-1 expressing Jurkat cells. As shown in FIGS. 3A-3B, the threevariants were indistinguishable in the competition experiment. Theresults show that the three chimeric mAbs (Cys, Tyr, Ser) competeequally well with the binding of the labeled murine mAb BAP049. Theslight difference between the chimeric mAb curves and the murine mAbcurve is probably due to the different methods used for determining mAbconcentrations. The concentration of the murine mAb was determined byOD280 measurement, whereas the chimeric mAb concentrations insupernatants were determined with an ELISA using an IgG4 standard. Thegermline residue Tyr was selected for humanized antibodies.

The amino acid sequences of the heavy and light chains for chimeric mAbBAP049-chi (Cys) are shown in Table 1. The nucleotide sequences of theheavy and light chains for chimeric mAb BAP049-chi (Cys) are shown inTable 1. In BAP049-chi (Tyr) and BAP049-chi (Ser), the unpaired Cysresidue at position 102 of the LC were replaced with a Tyr or Serresidue.

Example 1.4: Humanized Antibody Clones

As shown in FIG. 4, the process of humanization yielded sixteen cloneswith binding affinities comparable to that of the chimeric antibody. Inaddition to binding data, for each clone, the VR sequences were providedalong with a sample of the mAb. The samples had been prepared bytransient transfections of CHO cells and were concentrated tissueculture supernatants. The antibody concentrations in the solutions hadbeen determined by an IgG4-specific ELISA.

As shown in FIG. 5, the sixteen unique clones are combinations of fourunique HC sequences and nine unique LC sequences. For the HC FW regions,the HC sequences are combinations of one of two different VHFW1, one ofthree different VHFW2, and one of two different VHFW3 sequences. For theLC FW regions, the LC sequences are combinations of one of fivedifferent VLFW1, one of three different VLFW2, and one of four differentVLFW3 sequences. The amino acid and nucleotide sequences of the heavyand light chain variable domains for the humanized BAP049 clones areshown in Table 1. The amino acid and nucleotide sequences of the heavyand light chain CDRs of the humanized BAP049 clones are also shown inTable 1.

FIG. 5 indicates that the samples varied in the concentration of themAb, ranging from 7.9 μg/mL to 61.5 μg/mL. These numbers wererepresentative of several transient expression experiments.

Example 1.5: Analysis of Humanized Clones Example 1.5.1: Analysis ofBinding Activity and Binding Specificity

The binding activity and specificity was measured in a competitionbinding assay using a constant concentration of Alexa 488-labeled murinemAb, serial dilutions of the test mAbs, and PD-1-expressing 300.19cells. Incubations with the mAb mixtures having different concentrationratios of test mAb to labeled mAb was at 4° C. for 30 min. Bound labeledmurine mAb was then quantified using a FACS machine. The experiment wasperformed twice. The results are shown in FIGS. 6A-6B.

Within the accuracy of the experiment, all humanized clones show similaractivity for competing with binding of labeled murine mAb. The activityis also comparable to the activity of the parent murine mAb and chimericmAb. MAbs were ranked relative to each other. For example, it can be aweaker competitor if in both experiments the curve of a certain clone isto the right of the chimeric mAb curve or it can be a better competitorif the curve of a certain clone is to the left of the chimeric mAbcurve. Such a ranking system was used in FIG. 7.

Example 1.5.2: Sequence Analysis

Based on structural features, the sixteen humanized mAbs were dividedinto four groups and ranked from A to E. The results are shown in FIG.7.

Example 1.5.3: Selection of Humanized Clones

FIG. 7 summarizes the data which was considered for the selection ofhumanized clones. Expression data (2^(nd) column), the diversity in thecomposition of the variable regions (3^(rd) column), relative rankingsin binding studies (4^(th) and 5^(th) columns), and structural analysis(6^(th) column), were considered.

Selected clones were further tested for their ability to block thebinding of PD-L1 and PD-L2 to PD-1 and for enhancing T cell activity invitro assays with human PBMC.

Example 1.5.4: Blocking of Ligand Binding

Murine anti-PD-1 mAb blocks the binding of the natural ligands PD-L1 andPD-L2 to PD-1 expressed on cells at low concentrations. Whether thehumanized clones had preserved the blocking capacity of the parentmurine mAb was tested in comparative experiments with murine andchimeric antibodies.

The blocking capacity of the mAbs was evaluated in a competition bindingassay using a constant concentration of PD-L1-huIgG1 Fc fusion proteinor PD-L2-hulgG1 Fc fusion protein, serial dilutions of the mAbs to betested, and PD-1-expressing 300.19 cells. Incubation was at 4° C. for 30min. Bound ligand fusion proteins were detected with PE-conjugatedF(ab′)2 fragment of goat anti-human IgG which doesn't recognize IgG4mAbs (Southern Biotech 2043-09), and flow cytometry. The results areshown in FIGS. 8A-8B.

Within the accuracy of the experiments, the humanized clones, chimericantibody and murine parent mAb demonstrated comparable blocking activityfor both the PD-L1 and PD-L2 ligands.

Example 1.5.5: T-Cell Epitope Analysis

Humanized mAbs were analyzed for T cell epitopes using Epibase™. Thealgorithm analyzes each possible peptide (each 10-mer along the proteinadvancing by one amino acid) for binding to HLA class II. It estimatesfree energy of binding (ΔG_(bind)) for each peptide and calculates aputative K_(D) (ΔG_(bind)=RT lnK_(D)). Then peptides are labeled S, M,or N for strong, medium, and non-binders. Threshold values used for thisclassification are different for each allotype.

The data was normalized to a risk score. The overall “risk score” is thesum of all potential epitopes to all tested alleles, weighted by theaffinities of the respective peptides but leaving out all potentialepitopes in germ line sequences (lower value therefor is “better”).

There are roughly three categories of mAbs, derived from a large set ofmAbs of different composition as described below.

Risk score of around 500: fully human mAbs generated from humans,“humanized” mice, and phage libraries (“values below 500 are really goodeven for fully human antibodies”).

Humanized mAbs specifically engineered (even the CDRs) to have a lowscore are typically in the 500-700 risk category.

Risk score around 900: typical CDR-grafted antibodies, which have fullymurine CDRs with or without changes in the FW region; approvedCDR-grafted mAbs are basically all in this category.

Risk score around 1500: chimeric mAbs.

The results for selected humanized BAP049 mAbs are:

Clone No. Risk score 01 476 05 479 08 472 09 503 10 583 11 614

Selected humanized clones have low scores. Typically, values below 500indicate low risk of immunogenicity even for fully human antibodies. Forexample, the human mAb, adalimumab (Humira®), has a score of 654, whichis relatively high for human mAbs (at the upper end of the Gaussiancurve) but low in comparison to a typical CDR-grafted mAb.

SUMMARY AND CONCLUSIONS

Murine anti-PD-1 monoclonal antibody, BAP049, was humanized. Thetechnology entails the cloning of the murine CDRs in-frame into anordered library of human germ line variable region frameworks,expressing the library of cloned variable regions as intact IgG4(S228P)humanized mAbs in CHO cells, and selecting clones that bind withcomparable or higher affinity to the target as the parent mAb.Therefore, the murine CDRs were asked to select proper human germlineframework sequences that preserve their conformations and thus thebinding affinity and specificity of the parent murine mAb. The sequencesand test samples of sixteen humanized mAbs with unique variable regionsequences were obtained, which had passed a binding test withPD-1-transfected CHO cells. These clones were further analyzed for theirbiological functions (e.g., antigen binding and ligand blocking),structural features, and transcient expression in CHO cells.

Example 2: Expression of Humanized Anti-PD-1 Antibody, BAP049

Five humanized clones described in Example 1 were selected forevaluation of expression in Chinese Hamster Ovary (CHO) cells.

Single gene vectors (SGVs) were constructed using Lonza's GS Xceedvectors (IgG4proΔk for heavy chain and Kappa for light chain). The SGVswere amplified and transiently co-transfected into CHOK1SV GS-KO cellsfor expression at a volume of 2.8 L.

Expression cultures were harvested Day 6 post-transfection and clarifiedby centrifugation and sterile filtration. The clarified cell culturesupernatant was purified using one-step Protein A chromatography.Product quality analysis in the form of SE-HPLC, SDS-PAGE, IEF, and LALwas carried out using purified material at a concentration of 1 mg/mlincluding an antibody as a control sample.

Example 2.1: Vector Construction

The sequences of the light and heavy chain variable domain encodingregions were synthesised by GeneArt AG. Light chain variable domainencoding regions were sub-cloned into pXC-Kappa and heavy chain variabledomain encoding regions into pXC-IgG4pro AK vectors respectively usingthe N-terminal restriction site Hind III and the C-terminal restrictionsites BsiWI (light chain) and ApaI (heavy chain). Positive clones werescreened by PCR amplification (primers 1053: GCTGACAGACTAACAGACTGTTCC(SEQ ID NO: 226) and 1072: CAAATGTGGTATGGCTGA (SEQ ID NO: 227)) andverified by restriction digest (using a double digest of EcoRI-HF andHindIII-HF) and nucleotide sequencing of the gene of interest.

Example 2.2: DNA Amplification

A single bacterial colony was picked into 15 ml Luria Bertani (LB)medium (LB Broth, Sigma-Aldrich, L7275) containing 50 μg/ml ampicillinand incubated at 37° C. overnight with shaking at 220 rpm. The resultingstarter culture was used to inoculate 1 L Luria Bertani (LB) mediumcontaining 50 μg/ml ampicillin and incubated at 37° C. overnight withshaking at 220 rpm. Vector DNA was isolated using the QIAGEN PlasmidPlus Gigaprep system (QIAGEN, 12991). In all instances, DNAconcentration was measured using a Nanodrop 1000 spectrophotometer(Thermo-Scientific) and adjusted to 1 mg/ml with EB buffer (10 mMTris-C1, pH 8.5). DNA quality for the single gene vectors was assessedby measuring the absorbance ratio A260/A280. This was found to bebetween 1.88 and 1.90.

Example 2.3: Culture of CHOK1SV GS-KO Cells

CHOK1SV GS-KO cells were cultured in CD-CHO media (Invitrogen,10743-029) supplemented with 6 mM glutamine (Invitrogen, 25030-123).Cells were incubated in a shaking incubator at 36.5° C., 5% CO₂, 85%humidity, 140 rpm. Cells were routinely sub-cultured every 3-4 days,seeding at 2×10⁵ cells/ml and were propagated in order to havesufficient cells available for transfection. Cells were discarded bypassage 20.

Example 2.4: Transient Transfections of CHOK1SV GS-KO Cells

Transient transfections were performed using CHOK1SV GS-KO cells whichhad been in culture a minimum two weeks. Cells were sub-cultured 24 hprior to transfection and cell viability was >99% at the time oftransfection.

All transfections were carried out via electroporation using a GenePulse MXCell (Bio-Rad), a plate based system for electroporation. Foreach transfection, viable cells were resuspended in pre-warmed media to2.86×10⁷ cells/ml. 80 μg DNA (1:1 ratio of heavy and light chain SGVs)and 700 μl cell suspension were aliquotted into each cuvette/well. Cellswere electroporated at 300 V, 1300 μF. Transfected cells weretransferred to pre-warmed media in Erlenmeyer flasks and thecuvette/wells rinsed twice with pre-warmed media which was alsotransferred to the flasks. Transfected cell cultures were incubated in ashaking incubator at 36.5° C., 5% CO₂, 85% humidity, 140 rpm for 6 days.Cell viability and viable cell concentrations were measured at the timeof harvest using a Cedex HiRes automated cell counter (Roche).

Example 2.5: Protein a Affinity Chromatography

Cell culture supernatant was harvested and clarified by centrifugationat 2000 rpm for 10 min, then filtered through a 0.22 μm PES membranefilter. Clarified supernatant was purified using a pre-packed 5 mlHiTrap MabSelect SuRE column (GE Healthcare, 11-0034-94) on an AKTApurifier (10 ml/min). The column was equilibrated with 50 mM sodiumphosphate, 125 mM sodium chloride, pH 7.0 (equilibration buffer) for 5column volumes (CVs). After sample loading, the column was washed with 2CVs of equilibration buffer followed by 3 CVs of 50 mM sodium phosphate,1 M sodium chloride pH 7.0 and a repeat wash of 2 CVs of equilibrationbuffer. The Product was then eluted with 10 mM sodium formate, pH 3.5over 5 CVs. Protein containing, eluted fractions were immediately pHadjusted to pH 7.2 and filtered through a 0.2 μm filter.

A single protein-containing peak was observed during the elution phase.This peak was shown to contain the mAb, when analyzed by SE-HPLC andSDS-PAGE. Recovered protein yield is shown in Table 5. The clonesexpressed transiently in a range from 32.4 to 43.0 mg/L.

TABLE 5 Summary of yield, titre, monomer content and endotoxin levelsMonomer Endotoxin levels Product Yield* (mg) Titre* (mg/L) Content (%)(EU/mg) Clone A 107.5 38.38 93.94 0.04 Clone B 93.8 33.50 95.28 0.63Clone C 90.7 32.38 97.83 0.04 Clone D 108.9 38.88 96.53 0.35 Clone E120.4 43.00 97.73 0.14 *Post Protein A purification

Example 2.6: SE-HPLC Analysis

Samples of Protein A purified antibodies were analyzed in duplicate bySE-HPLC on an Agilent 1200 series HPLC system, using a Zorbax GF-250 4μm 9.4 mm ID×250 mm column (Agilent). Aliquots of sample at aconcentration of 1 mg/ml were filtered through a 0.2 μm filter prior toinjection. 80 μl aliquots were injected respectively and run at 1 ml/minfor 15 minutes. Soluble aggregate levels were analysed using Chemstation(Agilent) software.

Chromatography profiles with retention time showing the percentage ofthe overall detected peak areas were obtained for the tested antibodiesand a control IgG4 antibody. The products show a single protein peak atapproximately 8.65 to 8.72 min comparable to the human IgG4 antibodycontrol (about 8.64 min) and consistent with a monomeric antibody. Smallamounts (up to about 4-5%) of higher molecular weight impurities,consistent with soluble aggregates, were detected at retention timesbetween about 7.43 and 8.08 min.

Example 2.7: SDS-PAGE Analysis

Reduced samples were prepared for analysis by mixing with NuPage 4×LDSsample buffer (Invitrogen, NP0007) and NuPage 10× sample reducing agent(Invitrogen, NP0009), and incubated at 70° C., 10 min. For non-reducedsamples, the reducing agent and heat incubation were omitted. Sampleswere electrophoresed on 1.5 mm NuPage 4-12% Bis-Tris Novex pre-cast gels(Invitrogen, NP0335PK2) with NuPage MES SDS running buffer underdenaturing conditions. 10 μl aliquots of SeeBlue Plus 2 pre-stainedmolecular weight standard (Invitrogen, LC5925) and a control IgG4antibody at 1 mg/ml were included on the gel. 1 μl of each sample at 1mg/ml were loaded onto the gel. Once electrophoresed, gels were stainedwith InstantBlue (TripleRed, ISB01L) for 30 min at room temperature.Images of the stained gels were analysed on a BioSpectrum Imaging System(UVP).

The analysis confirmed the presence of the antibody products and goodlevels of purity. Under non-reducing conditions, a predominant proteinband close to 98 kDa was observed comparable with the control IgG4antibody. The control IgG4 antibody and one tested clone display anadditional fainter band corresponding to a heavy plus light chainhalf-antibody at approximately 70 kDa under non-reducing conditions.This is expected for the control antibody. Two bands were observed underreducing conditions consistent with the size of heavy (close to theposition of the 49 kDa marker) and light chains (close to the positionof the 28 kDa marker) and comparable with the bands found for thecontrol IgG4 antibody.

Example 2.8: Iso-Electric Focussing (IEF) Analysis

Non-reduced samples of Protein A purified antibody were electrophoresedas described below.

5 μg of Protein A purified samples were electrophoresed on a 1.0 mmNovex pH 3-10 gradient gel (Invitrogen, EC66552BOX) using manufacturersrecommended running conditions. A 10 μl aliquot of IEF pH 3-10 markers(Invitrogen, 39212-01) was included on the gel. Once electrophoresed,gels were fixed with 10% TCA solution for 30 min and then stained withInstantBlue (TripleRed, ISB01L) over night at room temperature. Imagesof the stained gels were analysed on a BioSpectrum Imaging System (UVP).

As shown in Table 6, the tested clones show charge isoforms between pH7.4 and 8.0 markers. The detected charge isoforms are slightly morebasic than the theorectically calculated pIs for these antibodies whichwere predicted to be between 6.99 and 7.56. The general shift to morebasic charge isoforms suggests the presence of post-translationalmodifications such as glycosylation on the molecules. Clone C and CloneE show comparable charge isoforms, which is also consistent with thetheorectically calculated pI being the same for both (6.99). The controlIgG4 antibody behaved as expected.

TABLE 6 Charge isoforms as detected by Novex IEF analysis pI ofpredominant Acidic charge Basic charge Product charge isoform* isoforms*isoforms* Clone A 7.6 2x; 7.5 to 7.55 7.7 Clone B 7.75 2x; 7.5 to 7.67.8 Clone C 7.5 2x; 7.4 to 7.5 7.55 Clone D 8.0 7.9 8.1 Clone E 7.5 2x;7.4 to 7.5 7.55 *pI readings are estimated from the staining positionscorrelated against the IEF 3-10 marker.

Example 2.9: Endotoxin Analysis

Endotoxin levels of purified proteins were measured at finalconcentrations (up to 3.44 mg/ml) using an Endosafe-PTS instrument, acartridge based method based on the LAL assay (Charles River).

As shown in Table 5, the endotoxin content was found to range from 0.04to 0.63 EU/mg.

CONCLUSION

GS single gene expression vectors for selected humanized anti-PD-1 mAbswere constructed and used to transiently transfect CHOK1SV GS-KO cells.2.6 to 2.8 litres of expression culture were incubated under standardconditions for 6 days and the resulting cell culture supernatantpurified using Protein A chromatography. Post-purification titres areindicated in Table 5 and were found to be ranging from 32.38 to 43.0mg/L. The recovered yields range from 90.7 to 120.4 mg.

SDS-PAGE and SE-HPLC analysis indicated the presence of a small amount(up to 6.06%) of soluble aggregates present in the products beingpredominantly consistent with dimeric antibody for the mAb. The mAbsalso showed higher molecular weight impurities at retention timesconsistent with that of trimeric antibodies.

Iso-electric focusing detected a number of charge isoforms for all mAbs.The mAbs showed isoforms generally more basic when based ontheoretically calculated pI for these molecules indicating some level ofpost translation modification. The mAbs were found to be comparable totheir theoretically calculated pI values.

The endotoxin levels for all samples were measured prior to provision ofsamples and found to be below 0.63 EU/mg.

Example 3: Characterization of Murine and Humanized Anti-PD-1 AntibodiesExample 3.1: Characterization of Murine Anti-PD-1 Antibody

The binding affinity of murine anti-PD-1 antibody BAP049 to PD-1 wasinvestigated. The murine anti-PD-1 antibody binds to human PD-1-Igfusion protein with a K_(D) of 0.04 nM as measured by ELISA. As shown byFACS analyses, the murine anti-PD-1 antibody binds to human PD-1transfected Jurkat cells with a K_(D) of 0.06 nM, to cynomolgus T cells(e.g., CD3/CD28 activated CD4 T cells) with a K_(D) of 0.4 nM, and tocells transfected with cynomolgus PD-1 with a K_(D) of 0.6 nM.

The blocking activity of murine anti-PD-1 antibody BAP049 was examinedby competition binding assays. The murine anti-PD-1 antibody blockedPD-L1 binding to human PD-1-expressing 300.19 cells with an IC50 of 0.3nM. It blocked PD-L2 binding to human PD-1-expressing 300.19 cells withan IC50 of 0.9 nM.

The effect of murine anti-PD-1 antibody BAP049 on interferon gamma(IFN-γ) expression was tested. The murine anti-PD-1 antibody resulted in2.3±1.1 fold increase in IFN-γ expression on cells stimulated withanti-CD3 (0.1 μg/mL), 2.5±2.0 fold increase on cells stimulated withStaphylococcal enterotoxin B (SEB) (3 pg/mL), and 2.8±0.8 fold increaseon cells stimulated with CMV peptides.

The murine anti-PD-1 antibody BAP049 was also found to increaseproliferation of CD8⁺ T cells activated with CMV peptides as indicatedby the percentages of CD8⁺ cells that passed through at least certainnumber (n) of cell divisions (e.g., n=2, 4, 6).

Example 3.2: Characterization of Humanized Anti-PD-1 Antibody BindingAffinity and Specificity

The binding of an exemplary humanized anti-PD-1 antibody on human PD-1protein was measured using Biacore method. The results are: Ka=2.78×10⁵M⁻¹s⁻¹; Kd=2.13×10⁻⁴ s⁻¹; K_(D)=0.0827±0.005505 nM.

The binding of the same humanized anti-PD-1 antibody on humanPD-1-expressing 300.19 cells was measured using FACS analysis. Theresult shows that the anti-PD-1 antibody (human IgG4) binds with highaffinity to human PD-1 compared to a human IgG4 isotype control.

The exemplary humanized anti-PD-1 antibody was found to exhibit highaffinity to cynomolgus PD-1 protein and cynomolgus PD-1-expressing300.19 cells. As measured by Biacore method, the anti-PD-1 antibodybinds to cynomolgus PD-1 with a K_(D) of 0.093±0.015 nM. The bindingaffinity to cynomolgus PD-1 is comparable to its binding affinity tohuman PD-1.

Additional binding analyses show that the exemplary humanized anti-PD-1antibody is not cross-reactive with mouse PD-1 or cross-reactive withparental cell line.

Blocking of Interactions Between PD-1 and its Ligands

The ability of the exemplary humanized anti-PD-1 antibody to block theinteractions between PD-1 and both of its known ligands, PD-L1 and PD-L2was examined. The results show that the anti-PD-1 antibody blocked thebinding of PD-L1 and PD-L2 on human PD-1-expressing 300.19 cellscompared to human IgG4 isotype control and no antibody control. Theanti-PD-1 antibody blocked PD-L1 binding on the 300.19 cells with anIC50 of 0.94±0.15 nM. The same antibody blocked PD-L2 binding on the300.19 cells with an IC50 of 1.3±0.25 nM.

Cellular Activity

The ability of the exemplary humanized anti-PD-1 antibody to enhance theStaphylococcal enterotoxin B (SEB)-stimulated expression of IL-2 wastested in human whole blood ex vivo assay. Diluted human whole blood wasincubated with the anti-PD-1 antibody in the presence or absence of SEBat 37° C. for 48 hours prior to IL-2 measurement. The result shows thatthe anti-PD-1 antibody increased SEB-stimulated IL-2 expression by2.28±0.32 fold compared to a human IgG4 isotype control (25 μg/ml SEB;n=5 donors).

Example 4: Patient Selection Based on PD-L1/CD8/IFN-γ Status

For each of several types of cancer, samples from multiple patients weretested for PD-L1/CD8/IFN-γ status. Each sample was classified as:triple-negative for PD-L1/CD8/IFN-γ, single or double positive for thesemarkers, or triple-positive for these markers. FIG. 11 shows that inthis experiment, within a population of patients, the following types ofcancer are frequently triple-positive for PD-L1/CD8/IFN-γ: Lung cancer(squamous), lung cancer (adenocarcinoma), head and neck cancer, cervicalcancer (squamous), stomach cancer, thyroid cancer, melanoma, andnasopharyngeal cancer. Patients having these types of cancer are goodcandidates for therapy with anti PD-1 antibodies and combinationtherapies as described herein. The likelihood of successful treatmentcan be further boosted by determining which patients are triple-positivefor PD-L1/CD8/IFN-γ, and treating the triple-positive patients with antiPD-1 antibodies and combination therapies as described herein.

FIG. 12 shows that within a population of patients, the following typesof cancer are rarely triple positive for PD-L1/CD8/IFN-γ: ER+ breastcancer and pancreatic cancer. Notably, even in cancers that aregenerally not positive for PD-L1/CD8/IFN-γ, one can increase thelikelihood of successful treatment by determining which patients aretriple-positive for PD-L1/CD8/IFN-γ, and treating the triple-positivepatients with anti PD-1 antibodies and combination therapies asdescribed herein.

FIG. 13 shows the proportion of breast cancer patients that are triplepositive for PD-L1/CD8/IFN-γ. Considering breast cancer in general, theproportion of triple-positives is somewhat low. However, when onefocuses only on IM-TN breast cancer, it can be seen that a much largerpercentage of patients is triple positive for PD-L1/CD8/IFN-γ. IM-TNbreast cancer is particularly difficult to treat with conventionaltherapies. The discovery that IM-TN breast cancer is oftentriple-postive for PD-L1/CD8/IFN-γ opens up new avenues of therapy forthis cancer with anti PD-1 antibodies and combination therapies asdescribed herein.

FIG. 14 shows the proportion of colon cancer patients that are triplepositive for PD-L1/CD8/IFN-γ. Considering colon cancer in general, theproportion of triple-positive is somewhat low. However, when one focusesonly on MSI-high (high microsatellite instability) breast cancer, it canbe seen that a much larger percentage of patients is triple positive forPD-L1/CD8/IFN-γ. MSI levels can be assayed using, e.g., commerciallyavailable PCR-based methods.

Gastric cancer samples were tested for levels of PD-L1/CD8/IFN-γ (datanot shown). It was found that in MSI-high or EBV+ gastric cancers, about49% were positive for PD-L1, and a high proportion of the PD-L1-positivecells were triple positive for PD-L1/CD8/IFN-γ. It was also found that aproportion of PD-L1-positive cells and PD-L1/CD8/IFN-γ positive cellswere also positive for PIK3CA. This finding suggests that these cancersmay be treated with a PD-1 antibody, optionally in combination with aPIK3 therapeutic.

MSI-high CRC samples were tested for a combination of markers (data notshown). It was found that in MSI-high CRC samples, a high proportion ofthe PD-L1/CD8/IFN-γ samples are also positive for LAG-3, PD-1 (alsocalled PDCD1), RNF43, and BRAF. This finding suggests that these cancersmay be treated with a PD-1 antibody, optionally in combination with atherapeutic that targets one or more of LAG-3, PDCD1, RNF43, and BRAF.

Squamous cell lung cancers were tested for a combination of markers(data not shown). It was found that in squamous cell lung cancersamples, a high proportion of the PD-L1/CD8/IFN-γ samples are alsopositive for LAG-3. This finding suggests that these cancers may betreated with a PD-1 antibody, optionally in combination with atherapeutic that targets LAG-3, e.g., a LAG-3 antibody.

Papillary thyroid cancers were tested for a combination of markersincluding the BRAF V600E mutation (data not shown). It was found that ahigh proportion of thyroid cancer samples that are positive for PD-L1are also positive for BRAF V600E. This finding suggests that thesecancers may be treated with a PD-1 antibody, optionally in combinationwith a therapeutic that targets BRAF.

Example 5: Patient Selection Based on PD-L1 Status

To enable broad examination of cancer indications for PD-1/PD-L1 basedtherapies, we evaluated PD-L1 expression at both the protein and mRNAlevel in human cancers including both lung and hepatic tumors.

PD-L1 protein expression was evaluated in a set of formalin-fixedparaffin-embedded non-small cell lung (NSCLC) adenocarcinoma (ACA),NSCLC squamous cell carcinoma (SCC), and hepatocellular carcinoma (HCC)tumors by immunohistochemistry (IHC). PD-L1 expression was scoredsemi-quantitatively by a manual histo-score (H-score) methodology basedon staining intensity and percentage of positive tumor cells. In our IHCanalysis, PD-L1 positivity (PD-L1+) was defined as an H-score ≥20. Inparallel, PD-L1 mRNA expression data was examined from The Cancer GenomeAtlas (TCGA) in these same indications (503 NSCLC ACA, 489 NSCLC SCC,and 191 HCC) and analyzed by comparing the expression in matched normaltissues from TCGA.

With RNAseq analysis, data was calculated as log 2 (RPKM+0.1) after RSEMnormalization, utilizing OmicSoft RNASeq pipelines across TCGA tumorindications. The expression of PD-L1 is elevated in NSCLC ACA and SCC,relative to that in HCC. By overlaying the distributions and comparingthe expression levels across all indications in TCGA, we rankedoverexpression profiles for PD-L1 and found the TCGA HCC cohort to havemuch reduced PD-L1 mRNA levels, with a median level of −0.8 compared to1.3 for ACA and 1.5 for SCC, which amounts to more than a 2-fold changeof median level expression. With RNAseq, our analysis defines 50% ofNSCLC adenocarcinoma, 54% of NSCLC squamous cell carcinoma, and 6% ofHCC as high expressers for PD-L1.

Tumor cell PD-L1 protein expression was measured in 45 lungadenocarcinoma (ACA) samples, 47 lung squamous cell carcinoma (SCC)samples, and 36 hepatocellular carcinoma (HCC) samples. 16/45 (35.6%)lung ACA, 21/47 (44.7%) lung SCC were PD-L1 positive. In contrast, PD-L1positivity was seen in only 2/36 (5.6%) HCC samples.

In summary, with IHC and RNAseq analysis in large and independent humanNSCLC and HCC sample sets, we have found PD-L1 expression to be moreenriched in NSCLC than in HCC. Within NSCLC, there are comparablefindings between adenocarcinoma and squamous cell carcinomas.Importantly, amongst the large number of samples (128 for IHC and 1183for RNAseq) in the 3 indications, very good concordance is observedbetween protein- and mRNA-based analyses. Our finding thus establishesthe basis for large scale mRNA-based data mining in TCGA for indicationsand patient segments that may be enriched for responses toPD-1/PD-L1-based immune therapies.

Example 6: Effects of Targeted Agents on PD-L1 Modulation

This example evaluates the effects of selected therapeutic agents (e.g.,a cMET inhibitor, a MEK inhibitor, a bRAF inhibitor, and an ALKinhibitor) on PD-L1 (CD274) modulation. Compound A17 can be prepared asdisclosed in Example 21 of U.S. Pat. No. 8,420,645. The followingcompounds: Compound A18 (ruxolitinib phosphate), Compound A23(ceritinib), Compound A34 (Binimetinib), and Compound A29 (Encorafenib)are available from Novartis AG, Basel, Switzerland. Selected therapeuticagents were examined by real time PCR and flow cytometry on PD-L1levels. Significant inhibition of PD-L1 by Compound A17, Compound A18,Compound A34, Compound A29, and Compound A23 on tumor cells wasobserved.

Compound A17 Downregulation of PD-L1 Protein in Non-Small Cell LungCancer Cells

PD-L1 (CD274) expression was analyzed in cancer cell lines treated withCompound A17. Cells were obtained from ATCC and cultured in vitrofollowing ATCC directions. The cell lines used were previouslycharacterized by the Cancer Cell Line Encyclopedia Project(http://www.broadinstitute.org/ccle/home).

Cells plated in six-well culture plates were treated with the CompoundA17 at different concentrations (10 nM, 100 nM, and 1000 nM) for 24, 48and 72 hours. Equal amount of vehicle (DMSO) was used as a control.Cells were washed with PBS and then harvested using a cell scraper.

For each reaction, 0.5-1×10⁶ cells were stained with 20 μL of anti-humanmonoclonal PD-L1—PE antibody, clone M1H1 (BD) for 30-60 minutes at 4° C.Cells were washed twice and data was acquired using a Canto II withFACSDiva software (BD Bioscience). Data analysis was performed usingFlowJo software (Tree Star). Mean fluorescence intensity (MFI) wasdetermined by gating on single cells. Unstained cells were used as agating control.

In vitro treatment of EBC-1 cells (Non-Small Cell Lung Cancer (NSCLC)with cMET amplification) with Compound A17 led to significantdownregulation of surface expression of PD-L1 as observed by flowcytometry (FIG. 15). The results presented herein suggest that CompoundA17 functions as a PD-L1/PD-1 inhibitor.

Compound A17, Compound A34, Compound A18, Compound A29, and Compound A23Downregulate PD-L1 mRNA

TaqMan RT PCR assays were developed to detect changes of expressionlevels of PD-L1 (CD274) in cell lines and xenograft tumors. mRNA wasisolated from frozen cell pellets or tumor fragments using the QiagenRNeasy Mini kit. Isolated RNA was frozen at −80° C. RNA quality waschecked and RNA was quantified using a 2100 Agilent Bioanalyzerfollowing the protocol for the Agilent RNA 6000 Nano Kit. cDNA wasprepared using a High Capacity RNA-to cDNA Kit (Applied Biosystems).

Real-time PCR reactions were carried out in 20 μl total volume,including 100 of Universal PCR master mix (Applied Biosystems), 10 ofhuman PD-L1 (CD274) probe/primer set (Applied Biosystems), and 8 μl ofcDNA. Each sample was run in triplicate. The amount of cDNA producedfrom 25-50 ng of RNA in the reverse transcription reaction was used ineach PCR reaction. Due to difference in mRNA levels between PD-L1 andGAPDH, the two real-time PCR reactions were done in separate tubes usingsame amount of cDNA. The real-time PCR reaction was run on the C1000Thermal Cycle (BioRad) with the cycle program as follows: a 10 minuteincubation at 95° C. followed by 40 cycles of 95° C. for 15 seconds and60° C. for 1 minute. After the reaction was complete, the PD-L1 averageCt was normalized relative to each Ct value from the GAPDH referencereaction. Each normalized logarithmic value was then converted into alinear value.

Inhibition of PD-L1 expression (mRNA) by Compound A17 was observed in aHs.746.T tumor (gastric cancer cell with cMET amplification & mutation)xenograft (FIG. 16). Inhibition of PD-L1 mRNA by Compound A23 wasobserved in H3122 (Non-Small Cell Lung Cancer (NSCLC) with ALKtranslocation) in vitro (FIG. 17). Downregulation of PD-L1 mRNA byCompound A29, and Compound A34 was observed in tumor xenograft modelsbearing LOXIMV1 (BRAF mutant melanoma, FIG. 18) and HEYA8 (KRAF mutantovarian cancer, FIG. 19) tumors, respectively. Downregulation of PD-L1mRNA by Compound A18 was observed in tumor xenograft models bearingUKE-1 (Myeloproliferative Neoplasm (MPN) line with JAK2V617F mutation,FIG. 20).

The results presented herein demonstrate a role of Compound A17,Compound A34, Compound A18, Compound A29, and Compound A23 in theregulation of immunecheckpoint molecules on cancer. The observedinhibition of PD-L1 expression by these agents suggests that thesetargeted agents may have immune-modulatory activities, in addition totheir effects on cancer signaling. Thus, the results presented hereinsuggest that administration of targeted agents with inhibitors ofimmunecheckpoint inhibitors such as PD-1, PD-L1, LAG-3 and/or TIM-3 willachieve a more potent reversal of the immunecheckpoint-mediated immunesuppression.

INCORPORATION BY REFERENCE

All publications, patents, and Accession numbers mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference.

EQUIVALENTS

While specific embodiments of the subject invention have been discussed,the above specification is illustrative and not restrictive. Manyvariations of the invention will become apparent to those skilled in theart upon review of this specification and the claims below. The fullscope of the invention should be determined by reference to the claims,along with their full scope of equivalents, and the specification, alongwith such variations.

1.-38. (canceled)
 39. A nucleic acid molecule comprising a firstnucleotide sequence that encodes a heavy chain variable region (VH), ora second nucleotide sequence that encodes a light chain variable region(VL), or both, of an antibody molecule capable of binding to humanProgrammed Death-1 (PD-1), wherein the antibody molecule comprises: (a)a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 33; (b) a VH comprising a VHCDR1 aminoacid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ IDNO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 aminoacid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQID NO: 32; (c) a VH comprising a VHCDR1 amino acid sequence of SEQ IDNO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 aminoacid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ IDNO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or (d) aVHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acidsequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO:3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, aVLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acidsequence of SEQ ID NO:
 32. 40. The nucleic acid molecule of claim 39,wherein the antibody molecule comprises a VH comprising a VHCDR1 aminoacid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ IDNO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 aminoacid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQID NO:
 32. 41. The nucleic acid molecule of claim 39, wherein theantibody molecule comprises a VH comprising a VHCDR1 amino acid sequenceof SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and aVHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence ofSEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO:
 33. 42.The nucleic acid molecule of claim 39, wherein the antibody moleculecomprises a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO:224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 aminoacid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acidsequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO:11, and a VLCDR3 amino acid sequence of SEQ ID NO:
 32. 43. A nucleicacid molecule comprising a first nucleotide sequence that encodes a VH,or a second nucleotide sequence that encodes a VL, or both, of abispecific antibody molecule having a first binding specificity for PD-1and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5,PD-L1 or PD-L2, wherein the bispecific antibody molecule comprises: (a)a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3amino acid sequence of SEQ ID NO: 33; (b) a VH comprising a VHCDR1 aminoacid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ IDNO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 aminoacid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQID NO: 32; (c) a VH comprising a VHCDR1 amino acid sequence of SEQ IDNO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 aminoacid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ IDNO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or (d) a VHcomprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence ofSEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ IDNO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3amino acid sequence of SEQ ID NO:
 32. 44. The nucleic acid molecule ofclaim 39, wherein the first and the second nucleotide sequences are inthe same nucleic acid molecule.
 45. The nucleic acid molecule of claim39, wherein the first and the second nucleotide sequences are inseparate nucleic acid molecules.
 46. The nucleic acid molecule of claim43, wherein the first and the second nucleotide sequences are in thesame nucleic acid molecule.
 47. The nucleic acid molecule of claim 43,wherein the first and the second nucleotide sequences are in separatenucleic acid molecules.
 48. An expression vector comprising the nucleicacid molecule of claim
 39. 49.-51. (canceled)
 52. An expression vectorcomprising the nucleic acid molecule of claim
 43. 53. A host cellcomprising the nucleic acid molecule of claim
 39. 54.-56. (canceled) 57.A host cell comprising the nucleic acid molecule of claim
 43. 58. Amethod of producing an antibody molecule, comprising culturing the hostcell of claim 53 under conditions suitable for gene expression. 59.-61.(canceled)
 62. A method of producing an antibody molecule, comprisingculturing the host cell of claim 57 under conditions suitable for geneexpression. 63.-89. (canceled)
 90. The nucleic acid molecule of claim39, wherein the antibody molecule comprises a VH comprising a VHCDR1amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VLcomprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 aminoacid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQID NO:
 33. 91. The nucleic acid molecule of claim 39, wherein the firstnucleotide sequence encodes a VH comprising an amino acid sequence atleast 85% identical to any of SEQ ID NOs: 38, 50, 82, or
 86. 92. Thenucleic acid molecule of claim 39, wherein the first nucleotide sequenceencodes a VH comprising the amino acid sequence of SEQ ID NO: 38, 50,82, or
 86. 93. The nucleic acid molecule of claim 39, wherein the secondnucleotide sequence encodes a VL comprising an amino acid sequence atleast 85% identical to any of SEQ ID NOs: 42, 46, 54, 58, 62, 66, 70,74, or
 78. 94. The nucleic acid molecule of claim 39, wherein the secondnucleotide sequence encodes a VL comprising the amino acid sequence ofSEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or
 78. 95. The nucleic acidmolecule of claim 39, wherein the first nucleotide sequence and thesecond nucleotide sequence encode, respectively: (a) a VH comprising theamino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acidsequence of SEQ ID NO: 54; (b) a VH comprising the amino acid sequenceof SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ IDNO: 42; (c) a VH comprising the amino acid sequence of SEQ ID NO: 38 anda VL comprising the amino acid sequence of SEQ ID NO: 66; (d) a VHcomprising the amino acid sequence of SEQ ID NO: 38 and a VL comprisingthe amino acid sequence of SEQ ID NO: 70; (e) a VH comprising the aminoacid sequence of SEQ ID NO: 50 and a VL comprising the amino acidsequence of SEQ ID NO: 70; (f) a VH comprising the amino acid sequenceof SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ IDNO: 46; (g) a VH comprising the amino acid sequence of SEQ ID NO: 50 anda VL comprising the amino acid sequence of SEQ ID NO: 46; (h) a VHcomprising the amino acid sequence of SEQ ID NO: 50 and a VL comprisingthe amino acid sequence of SEQ ID NO: 54; (i) a VH comprising the aminoacid sequence of SEQ ID NO: 38 and a VL comprising the amino acidsequence of SEQ ID NO: 58; (j) a VH comprising the amino acid sequenceof SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ IDNO: 62; (k) a VH comprising the amino acid sequence of SEQ ID NO: 50 anda VL comprising the amino acid sequence of SEQ ID NO: 66; (l) a VHcomprising the amino acid sequence of SEQ ID NO: 38 and a VL comprisingthe amino acid sequence of SEQ ID NO: 74; (m) a VH comprising the aminoacid sequence of SEQ ID NO: 38 and a VL comprising the amino acidsequence of SEQ ID NO: 78; (n) a VH comprising the amino acid sequenceof SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ IDNO: 70; (o) a VH comprising the amino acid sequence of SEQ ID NO: 82 anda VL comprising the amino acid sequence of SEQ ID NO: 66; or (p) a VHcomprising the amino acid sequence of SEQ ID NO: 86 and a VL comprisingthe amino acid sequence of SEQ ID NO:
 66. 96. The nucleic acid moleculeof claim 39, wherein the first nucleotide sequence comprises anucleotide sequence at least 85% identical to any of SEQ ID NOs: 39, 51,83, 87, 90, 95, or
 101. 97. The nucleic acid molecule of claim 39,wherein the first nucleotide sequence comprises the nucleotide sequenceof SEQ ID NO: 39, 51, 83, 87, 90, 95, or
 101. 98. The nucleic acidmolecule of claim 39, wherein the second nucleotide sequence comprises anucleotide sequence at least 85% identical to any of SEQ ID NOs: 43, 47,55, 59, 63, 67, 71, 75, 79, 93, 97, 99, 104, or
 106. 99. The nucleicacid molecule of claim 39, wherein the second nucleotide sequencecomprises the nucleotide sequence of SEQ ID NO: 43, 47, 55, 59, 63, 67,71, 75, 79, 93, 97, 99, 104, or
 106. 100. The nucleic acid molecule ofclaim 39, which comprises: (a) a first nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 39 and a second nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 55; (b) afirst nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 39 and a second nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 43; (c) a first nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 39 and a second nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 67; (d) afirst nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 39 and a second nucleotide sequence comprising the nucleotidesequence of any of SEQ ID NO: 71; (e) a first nucleotide sequencecomprising the nucleotide sequence of SEQ ID NO: 51 and a secondnucleotide sequence comprising the nucleotide sequence of any of SEQ IDNO: 71; (f) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 47; (g) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 51 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 47; (h) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 51 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 55; (i) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 59; (j) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 63; (k) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 51 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 67; (l) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 75; (m) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 79; (n) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 83 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 71; (o) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 83 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 67; (p) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 87 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 67; (q) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 90 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 93; (r) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 95 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 97; (s) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 90 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 99; (t) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 101 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 104; or (u) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 95 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO:
 106. 101. The nucleic acid molecule of claim 39, which encodes aheavy chain comprising an amino acid sequence at least 85% identical toany of SEQ ID NOs: 40, 52, 84, 88, 91, or
 102. 102. The nucleic acidmolecule of claim 39, which encodes a heavy chain comprising the aminoacid sequence of SEQ ID NO: 40, 52, 84, 88, 91, or
 102. 103. The nucleicacid molecule of claim 39, which encodes a light chain comprising anamino acid sequence at least 85% identical to any of SEQ ID NOs: 44, 48,56, 60, 64, 68, 72, 76, or
 80. 104. The nucleic acid molecule of claim39, which encodes a light chain comprising the amino acid sequence ofSEQ ID NO: 44, 48, 56, 60, 64, 68, 72, 76, or
 80. 105. The nucleic acidmolecule of claim 39, which encodes: (a) a heavy chain comprising theamino acid sequence of SEQ ID NO: 91 and a light chain comprising theamino acid sequence of SEQ ID NO: 44; (b) a heavy chain comprising theamino acid sequence of SEQ ID NO: 91 and a light chain comprising theamino acid sequence of SEQ ID NO: 56; (c) a heavy chain comprising theamino acid sequence of SEQ ID NO: 91 and a light chain comprising theamino acid sequence of SEQ ID NO: 68; (d) a heavy chain comprising theamino acid sequence of SEQ ID NO: 91 and a light chain comprising theamino acid sequence of SEQ ID NO: 72; (e) a heavy chain comprising theamino acid sequence of SEQ ID NO: 102 and a light chain comprising theamino acid sequence of SEQ ID NO: 72; (f) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 44; (g) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 48; (h) a heavy chain comprising theamino acid sequence of SEQ ID NO: 52 and a light chain comprising theamino acid sequence of SEQ ID NO: 48; (i) a heavy chain comprising theamino acid sequence of SEQ ID NO: 52 and a light chain comprising theamino acid sequence of SEQ ID NO: 56; (j) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 56; (k) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 60; (l) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 64; (m) a heavy chain comprising theamino acid sequence of SEQ ID NO: 52 and a light chain comprising theamino acid sequence of SEQ ID NO: 68; (n) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 68; (o) a heavy chain comprising theamino acid sequence of SEQ ID NO: 52 and a light chain comprising theamino acid sequence of SEQ ID NO: 72; (p) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 72; (q) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 76; (r) a heavy chain comprising theamino acid sequence of SEQ ID NO: 40 and a light chain comprising theamino acid sequence of SEQ ID NO: 80; (s) a heavy chain comprising theamino acid sequence of SEQ ID NO: 84 and a light chain comprising theamino acid sequence of SEQ ID NO: 72; (t) a heavy chain comprising theamino acid sequence of SEQ ID NO: 84 and a light chain comprising theamino acid sequence of SEQ ID NO: 68; or (u) a heavy chain comprisingthe amino acid sequence of SEQ ID NO: 88 and a light chain comprisingthe amino acid sequence of SEQ ID NO:
 68. 106. The nucleic acid moleculeof claim 39, which comprises a heavy chain nucleotide sequence at least85% identical to any of SEQ ID NOs: 41, 53, 85, 89, 92, 96, or
 103. 107.The nucleic acid molecule of claim 39, which comprises a heavy chainnucleotide sequence of SEQ ID NO: 41, 53, 85, 89, 92, 96, or
 103. 108.The nucleic acid molecule of claim 39, which comprises a light chainnucleotide sequence at least 85% identical to any of SEQ ID NOs: 45, 49,57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105, or
 107. 109. The nucleicacid molecule of claim 39, which comprises a light chain nucleotidesequence of SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100,105, or
 107. 110. The nucleic acid molecule of claim 39, whichcomprises: (a) a heavy chain nucleotide sequence of SEQ ID NO: 92 and alight chain nucleotide sequence of SEQ ID NO: 94; (b) a heavy chainnucleotide sequence of SEQ ID NO: 96 and a light chain nucleotidesequence of SEQ ID NO: 98; (c) a heavy chain nucleotide sequence of SEQID NO: 92 and a light chain nucleotide sequence of SEQ ID NO: 100; (d) aheavy chain nucleotide sequence of SEQ ID NO: 96 and a light chainnucleotide sequence of any of SEQ ID NO: 107; (e) a heavy chainnucleotide sequence of SEQ ID NO: 103 and a light chain nucleotidesequence of any of SEQ ID NO: 105; (f) a heavy chain nucleotide sequenceof SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 45;(g) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chainnucleotide sequence of SEQ ID NO: 49; (h) a heavy chain nucleotidesequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQID NO: 49; (i) a heavy chain nucleotide sequence of SEQ ID NO: 53 and alight chain nucleotide sequence of SEQ ID NO: 57; (j) a heavy chainnucleotide sequence of SEQ ID NO: 41 and a light chain nucleotidesequence of SEQ ID NO: 57; (k) a heavy chain nucleotide sequence of SEQID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 61; (l) aheavy chain nucleotide sequence of SEQ ID NO: 41 and a light chainnucleotide sequence of SEQ ID NO: 65; (m) a heavy chain nucleotidesequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQID NO: 69; (n) a heavy chain nucleotide sequence of SEQ ID NO: 41 and alight chain nucleotide sequence of SEQ ID NO: 69; (o) a heavy chainnucleotide sequence of SEQ ID NO: 53 and a light chain nucleotidesequence of any of SEQ ID NO: 73; (p) a heavy chain nucleotide sequenceof SEQ ID NO: 41 and a light chain nucleotide sequence of any of SEQ IDNO: 73; (q) a heavy chain nucleotide sequence of SEQ ID NO: 41 and alight chain nucleotide sequence of SEQ ID NO: 77; (r) a heavy chainnucleotide sequence of SEQ ID NO: 41 and a light chain nucleotidesequence of SEQ ID NO: 81; (s) a heavy chain nucleotide sequence of SEQID NO: 85 and a light chain nucleotide sequence of any of SEQ ID NO: 73;(t) a heavy chain nucleotide sequence of SEQ ID NO: 85 and a light chainnucleotide sequence of SEQ ID NO: 69; or (u) a heavy chain nucleotidesequence of SEQ ID NO: 89 and a light chain nucleotide sequence of SEQID NO: 69 (v) a heavy chain nucleotide sequence of SEQ ID NO: 92 and alight chain nucleotide sequence of SEQ ID NO: 94; (w) a heavy chainnucleotide sequence of SEQ ID NO: 96 and a light chain nucleotidesequence of SEQ ID NO: 98; (x) a heavy chain nucleotide sequence of SEQID NO: 92 and a light chain nucleotide sequence of SEQ ID NO: 100; (y) aheavy chain nucleotide sequence of SEQ ID NO: 103 and a light chainnucleotide sequence of SEQ ID NO: 105; or (z) a heavy chain nucleotidesequence of SEQ ID NO: 96 and a light chain nucleotide sequence of SEQID NO:
 107. 111. The nucleic acid molecule of claim 39, which encodes aFab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).
 112. The nucleicacid molecule of claim 39, further comprising a nucleotide sequenceencoding a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4.113. The nucleic acid molecule of claim 39, further comprising anucleotide sequence encoding a light chain constant region of kappa orlambda.
 114. The nucleic acid molecule of claim 39, further comprising anucleotide sequence encoding a human IgG4 heavy chain constant regionwith a Serine to Proline mutation at position 108 of SEQ ID NO: 212 or214, and a nucleotide sequence encoding a kappa light chain constantregion.
 115. The nucleic acid molecule of claim 39, further comprising anucleotide sequence encoding a human IgG1 heavy chain constant regionwith an Asparagine to Alanine mutation at position 180 of SEQ ID NO:216, and a nucleotide sequence encoding a kappa light chain constantregion.
 116. The nucleic acid molecule of claim 39, further comprising anucleotide sequence encoding a human IgG1 heavy chain constant regionwith an Aspartate to Alanine mutation at position 148 and a Proline toAlanine mutation at position 212 of SEQ ID NO: 217, and a nucleotidesequence encoding a kappa light chain constant region.
 117. The nucleicacid molecule of claim 39, further comprising a nucleotide sequenceencoding a human IgG1 heavy chain constant region with a Leucine toAlanine mutation at position 117 and a Leucine to Alanine mutation atposition 118 of SEQ ID NO: 218, and a nucleotide sequence encoding akappa light chain constant region.
 118. The nucleic acid molecule ofclaim 39, wherein the VH comprises the amino acid sequence of SEQ ID NO:38 and the VL comprises the amino acid sequence of SEQ ID NO:
 54. 119.The nucleic acid molecule of claim 39, wherein the VH comprises theamino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acidsequence of SEQ ID NO:
 70. 120. The nucleic acid molecule of claim 39,wherein the first nucleotide sequence comprises the nucleotide sequenceof SEQ ID NO: 95 and the second nucleotide sequence comprises thenucleotide sequence of SEQ ID NO:
 97. 121. The nucleic acid molecule ofclaim 39, wherein the first nucleotide sequence comprises the nucleotidesequence of SEQ ID NO: 95 and the second nucleotide sequence comprisesthe nucleotide sequence of SEQ ID NO:
 106. 122. The nucleic acidmolecule of claim 39, wherein the first nucleotide sequence encodes aheavy chain comprising the amino acid sequence of SEQ ID NO: 91 and thesecond nucleotide sequence encodes a light chain comprising the aminoacid sequence of SEQ ID NO:
 56. 123. The nucleic acid molecule of claim39, wherein the first nucleotide sequence encodes a heavy chaincomprising the amino acid sequence of SEQ ID NO: 91 and the secondnucleotide sequence encodes a light chain comprising the amino acidsequence of SEQ ID NO:
 72. 124. The nucleic acid molecule of claim 39,comprising a heavy chain nucleotide sequence of SEQ ID NO: 96 and alight chain nucleotide sequence of SEQ ID NO:
 98. 125. The nucleic acidmolecule of claim 39, comprising a heavy chain nucleotide sequence ofSEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO: 107.126. A nucleic acid molecule comprising a first nucleotide sequenceencoding a VH and a second nucleotide sequence encoding a VL, of anantibody molecule capable of binding to human PD-1, wherein the VHcomprises the amino acid sequence of SEQ ID NO: 38 and the VL comprisesthe amino acid sequence of SEQ ID NO:
 54. 127. An expression vectorcomprising the nucleic acid molecule of claim
 126. 128. A host cellcomprising the nucleic acid molecule of claim
 126. 129. A methodproducing an antibody molecule or fragment thereof, comprising culturingthe host cell of claim 128 under conditions suitable for geneexpression, thereby producing the antibody molecule or fragment thereof.130. A nucleic acid molecule comprising a first nucleotide sequenceencoding a VH and a second nucleotide sequence encoding a VL, of anantibody molecule capable of binding to human PD-1, wherein the VHcomprises the amino acid sequence of SEQ ID NO: 38 and the VL comprisesthe amino acid sequence of SEQ ID NO:
 70. 131. An expression vectorcomprising the nucleic acid molecule of claim
 130. 132. A host cellcomprising the nucleic acid molecule of claim
 130. 133. A methodproducing an antibody molecule or fragment thereof, comprising culturingthe host cell of claim 132 under conditions suitable for geneexpression, thereby producing the antibody molecule or fragment thereof.134. A nucleic acid molecule comprising a first nucleotide sequencecomprising the nucleotide sequence of SEQ ID NO: 95 and a secondnucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 97.135. A nucleic acid molecule comprising a first nucleotide sequencecomprising the nucleotide sequence of SEQ ID NO: 95 and a secondnucleotide sequence comprising the nucleotide sequence of SEQ ID NO:106.
 136. The nucleic acid molecule of claim 43, wherein the firstnucleotide sequence encodes a VH comprising the amino acid sequence ofSEQ ID NO: 38, 50, 82, or 86, or an amino acid sequence at least 85%identical thereto.
 137. The nucleic acid molecule of claim 43, whereinthe second nucleotide sequence encodes a VL comprising the amino acidsequence of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or 78, or anamino acid sequence at least 85% identical thereto.
 138. The nucleicacid molecule of claim 43, wherein the first nucleotide sequence and thesecond nucleotide sequence encode, respectively: (a) a VH comprising theamino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acidsequence of SEQ ID NO: 54; (b) a VH comprising the amino acid sequenceof SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ IDNO: 42; (c) a VH comprising the amino acid sequence of SEQ ID NO: 38 anda VL comprising the amino acid sequence of SEQ ID NO: 66; (d) a VHcomprising the amino acid sequence of SEQ ID NO: 38 and a VL comprisingthe amino acid sequence of SEQ ID NO: 70; (e) a VH comprising the aminoacid sequence of SEQ ID NO: 50 and a VL comprising the amino acidsequence of SEQ ID NO: 70; (f) a VH comprising the amino acid sequenceof SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ IDNO: 46; (g) a VH comprising the amino acid sequence of SEQ ID NO: 50 anda VL comprising the amino acid sequence of SEQ ID NO: 46; (h) a VHcomprising the amino acid sequence of SEQ ID NO: 50 and a VL comprisingthe amino acid sequence of SEQ ID NO: 54; (i) a VH comprising the aminoacid sequence of SEQ ID NO: 38 and a VL comprising the amino acidsequence of SEQ ID NO: 58; (j) a VH comprising the amino acid sequenceof SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ IDNO: 62; (k) a VH comprising the amino acid sequence of SEQ ID NO: 50 anda VL comprising the amino acid sequence of SEQ ID NO: 66; (l) a VHcomprising the amino acid sequence of SEQ ID NO: 38 and a VL comprisingthe amino acid sequence of SEQ ID NO: 74; (m) a VH comprising the aminoacid sequence of SEQ ID NO: 38 and a VL comprising the amino acidsequence of SEQ ID NO: 78; (n) a VH comprising the amino acid sequenceof SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ IDNO: 70; (o) a VH comprising the amino acid sequence of SEQ ID NO: 82 anda VL comprising the amino acid sequence of SEQ ID NO: 66; or (p) a VHcomprising the amino acid sequence of SEQ ID NO: 86 and a VL comprisingthe amino acid sequence of SEQ ID NO:
 66. 139. The nucleic acid moleculeof claim 43, wherein the first nucleotide sequence comprises thenucleotide sequence of SEQ ID NO: 39, 51, 83, 87, 90, 95, or 101, or anucleotide sequence at least 85% identical thereto.
 140. The nucleicacid molecule of claim 43, wherein the second nucleotide sequencecomprises the nucleotide sequence of SEQ ID NO: 43, 47, 55, 59, 63, 67,71, 75, 79, 93, 97, 99, 104, or 106, or a nucleotide sequence at least85% identical thereto.
 141. The nucleic acid molecule of claim 43, whichcomprises: (a) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 55; (b) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 43; (c) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 67; (d) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of any ofSEQ ID NO: 71; (e) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 51 and a second nucleotide sequence comprisingthe nucleotide sequence of any of SEQ ID NO: 71; (f) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 47; (g) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 51 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 47; (h) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 51 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 55; (i) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 59; (j) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 63; (k) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 51 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 67; (l) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 39 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 75; (m) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 39 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 79; (n) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 83 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO: 71; (o) a first nucleotide sequence comprising the nucleotidesequence of SEQ ID NO: 83 and a second nucleotide sequence comprisingthe nucleotide sequence of SEQ ID NO: 67; or (p) a first nucleotidesequence comprising the nucleotide sequence of SEQ ID NO: 87 and asecond nucleotide sequence comprising the nucleotide sequence of SEQ IDNO:
 67. 142. The nucleic acid molecule of claim 43, which encodes aheavy chain comprising the amino acid sequence of SEQ ID NO: 40, 52, 84,88, 91, or 102, or an amino acid sequence at least 85% identicalthereto.
 143. The nucleic acid molecule of claim 43, which encodes alight chain comprising the amino acid sequence of SEQ ID NO: 44, 48, 56,60, 64, 68, 72, 76, or 80, or an amino acid sequence at least 85%identical thereto.
 144. The nucleic acid molecule of claim 43, whichencodes: (a) a heavy chain comprising the amino acid sequence of SEQ IDNO: 91 and a light chain comprising the amino acid sequence of SEQ IDNO: 44; (b) a heavy chain comprising the amino acid sequence of SEQ IDNO: 91 and a light chain comprising the amino acid sequence of SEQ IDNO: 56; (c) a heavy chain comprising the amino acid sequence of SEQ IDNO: 91 and a light chain comprising the amino acid sequence of SEQ IDNO: 68; (d) a heavy chain comprising the amino acid sequence of SEQ IDNO: 91 and a light chain comprising the amino acid sequence of SEQ IDNO: 72; (e) a heavy chain comprising the amino acid sequence of SEQ IDNO: 102 and a light chain comprising the amino acid sequence of SEQ IDNO: 72; (f) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 44; (g) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 48; (h) a heavy chain comprising the amino acid sequence of SEQ IDNO: 52 and a light chain comprising the amino acid sequence of SEQ IDNO: 48; (i) a heavy chain comprising the amino acid sequence of SEQ IDNO: 52 and a light chain comprising the amino acid sequence of SEQ IDNO: 56; (j) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 56; (k) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 60; (l) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 64; (m) a heavy chain comprising the amino acid sequence of SEQ IDNO: 52 and a light chain comprising the amino acid sequence of SEQ IDNO: 68; (n) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 68; (o) a heavy chain comprising the amino acid sequence of SEQ IDNO: 52 and a light chain comprising the amino acid sequence of SEQ IDNO: 72; (p) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 72; (q) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 76; (r) a heavy chain comprising the amino acid sequence of SEQ IDNO: 40 and a light chain comprising the amino acid sequence of SEQ IDNO: 80; (s) a heavy chain comprising the amino acid sequence of SEQ IDNO: 84 and a light chain comprising the amino acid sequence of SEQ IDNO: 72; (t) a heavy chain comprising the amino acid sequence of SEQ IDNO: 84 and a light chain comprising the amino acid sequence of SEQ IDNO: 68; or (u) a heavy chain comprising the amino acid sequence of SEQID NO: 88 and a light chain comprising the amino acid sequence of SEQ IDNO:
 68. 145. The nucleic acid molecule of claim 43, which comprises aheavy chain nucleotide sequence of SEQ ID NO: 41, 53, 85, 89, 92, 96, or103, or a nucleotide sequence at least 85% identical thereto.
 146. Thenucleic acid molecule of claim 43, which comprises a light chainnucleotide sequence of SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81,94, 98, 100, 105, or 107, or a nucleotide sequence at least 85%identical thereto.
 147. The nucleic acid molecule of claim 43, whichcomprises: (a) a heavy chain nucleotide sequence of SEQ ID NO: 92 and alight chain nucleotide sequence of SEQ ID NO: 94; (b) a heavy chainnucleotide sequence of SEQ ID NO: 96 and a light chain nucleotidesequence of SEQ ID NO: 98; (c) a heavy chain nucleotide sequence of SEQID NO: 92 and a light chain nucleotide sequence of SEQ ID NO: 100; (d) aheavy chain nucleotide sequence of SEQ ID NO: 96 and a light chainnucleotide sequence of any of SEQ ID NO: 107; (e) a heavy chainnucleotide sequence of SEQ ID NO: 103 and a light chain nucleotidesequence of any of SEQ ID NO: 105; (f) a heavy chain nucleotide sequenceof SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 45;(g) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chainnucleotide sequence of SEQ ID NO: 49; (h) a heavy chain nucleotidesequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQID NO: 49; (i) a heavy chain nucleotide sequence of SEQ ID NO: 53 and alight chain nucleotide sequence of SEQ ID NO: 57; (j) a heavy chainnucleotide sequence of SEQ ID NO: 41 and a light chain nucleotidesequence of SEQ ID NO: 57; (k) a heavy chain nucleotide sequence of SEQID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 61; (l) aheavy chain nucleotide sequence of SEQ ID NO: 41 and a light chainnucleotide sequence of SEQ ID NO: 65; (m) a heavy chain nucleotidesequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQID NO: 69; (n) a heavy chain nucleotide sequence of SEQ ID NO: 41 and alight chain nucleotide sequence of SEQ ID NO: 69; (o) a heavy chainnucleotide sequence of SEQ ID NO: 53 and a light chain nucleotidesequence of any of SEQ ID NO: 73; (p) a heavy chain nucleotide sequenceof SEQ ID NO: 41 and a light chain nucleotide sequence of any of SEQ IDNO: 73; (q) a heavy chain nucleotide sequence of SEQ ID NO: 41 and alight chain nucleotide sequence of SEQ ID NO: 77; (r) a heavy chainnucleotide sequence of SEQ ID NO: 41 and a light chain nucleotidesequence of SEQ ID NO: 81; (s) a heavy chain nucleotide sequence of SEQID NO: 85 and a light chain nucleotide sequence of any of SEQ ID NO: 73;(t) a heavy chain nucleotide sequence of SEQ ID NO: 85 and a light chainnucleotide sequence of SEQ ID NO: 69; or (u) a heavy chain nucleotidesequence of SEQ ID NO: 89 and a light chain nucleotide sequence of SEQID NO:
 69. 148. The nucleic acid molecule of claim 43, which encodes aFab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).
 149. The nucleicacid molecule of claim 43, further comprising (a) a nucleotide sequenceencoding a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4, (b)a nucleotide sequence encoding a light chain constant region of kappa orlambda, or both (a) and (b).
 150. The nucleic acid molecule of claim 43,further comprising: (a) a nucleotide sequence encoding a human IgG4heavy chain constant region with a Serine to Proline mutation atposition 108 of SEQ ID NO: 212 or 214, and a nucleotide sequenceencoding a kappa light chain constant region; (b) a nucleotide sequenceencoding a human IgG1 heavy chain constant region with an Asparagine toAlanine mutation at position 180 of SEQ ID NO: 216, and a nucleotidesequence encoding a kappa light chain constant region; (c) a nucleotidesequence encoding a human IgG1 heavy chain constant region with anAspartate to Alanine mutation at position 148 and a Proline to Alaninemutation at position 212 of SEQ ID NO: 217, and a nucleotide sequenceencoding a kappa light chain constant region; or (d) a nucleotidesequence encoding a human IgG1 heavy chain constant region with aLeucine to Alanine mutation at position 117 and a Leucine to Alaninemutation at position 118 of SEQ ID NO: 218, and a nucleotide sequenceencoding a kappa light chain constant region.
 151. The nucleic acidmolecule of claim 43, wherein the VH comprises the amino acid sequenceof SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ IDNO:
 54. 152. The nucleic acid molecule of claim 43, wherein the VHcomprises the amino acid sequence of SEQ ID NO: 38 and the VL comprisesthe amino acid sequence of SEQ ID NO:
 70. 153. The nucleic acid moleculeof claim 43, wherein the first nucleotide sequence comprises thenucleotide sequence of SEQ ID NO: 95 and the second nucleotide sequencecomprises the nucleotide sequence of SEQ ID NO:
 97. 154. The nucleicacid molecule of claim 43, wherein the first nucleotide sequencecomprises the nucleotide sequence of SEQ ID NO: 95 and the secondnucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 106.155. The nucleic acid molecule of claim 43, wherein the first nucleotidesequence encodes a heavy chain comprising the amino acid sequence of SEQID NO: 91 and the second nucleotide sequence encodes a light chaincomprising the amino acid sequence of SEQ ID NO:
 56. 156. The nucleicacid molecule of claim 43, wherein the first nucleotide sequence encodesa heavy chain comprising the amino acid sequence of SEQ ID NO: 91 andthe second nucleotide sequence encodes a light chain comprising theamino acid sequence of SEQ ID NO:
 72. 157. The nucleic acid molecule ofclaim 43, comprising a heavy chain nucleotide sequence of SEQ ID NO: 96and a light chain nucleotide sequence of SEQ ID NO:
 98. 158. The nucleicacid molecule of claim 43, comprising a heavy chain nucleotide sequenceof SEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO:107.
 159. An expression vector comprising the nucleic acid molecule ofclaim
 151. 160. A host cell comprising the nucleic acid molecule ofclaim
 151. 161. A method producing an antibody molecule or fragmentthereof, comprising culturing the host cell of claim 160 underconditions suitable for gene expression, thereby producing the antibodymolecule or fragment thereof.
 162. An expression vector comprising thenucleic acid molecule of claim
 152. 163. A host cell comprising thenucleic acid molecule of claim
 152. 164. A method producing an antibodymolecule or fragment thereof, comprising culturing the host cell ofclaim 163 under conditions suitable for gene expression, therebyproducing the antibody molecule or fragment thereof.